Androgen modulators

ABSTRACT

The present invention is directed to a new class of 4-cyano-phenoxy-alkyl carboxyl derivatives and to their use as androgen receptor modulators. Other aspects of the invention are directed to the use of these compounds to decrease excess sebum secretions and to stimulate hair growth.

FIELD OF THE INVENTION

The present invention is directed to a new class of4-cyano-phenoxy-alkyl carboxyl derivatives and to their use as androgenreceptor modulators. Other aspects of the invention are directed to theuse of these compounds to decrease sebum secretion and to stimulate hairgrowth.

BACKGROUND OF THE INVENTION

Alopecia, or balding, is a common problem which medical science has yetto cure. While androgens are associated with balding, the physiologicalmechanism by which this hair loss occurs is not known. However, it isknown that hair growth is altered in individuals afflicted withalopecia.

Hair does not grow continuously but undergoes cycles of activityinvolving periods of growth, rest, and shedding. The human scalptypically contains from 100,000 to 350,000 hair fibers or shafts, whichundergo metamorphosis in three distinct stages:

(a) during the growth phase (anagen) the follicle (i.e. the hair root)penetrates deep into the dermis with the cells of the follicle dividingrapidly and differentiating in the process of synthesizing keratin, thepredominant component of hair. In non-balding humans, this growth phaselasts from one to five years;(b) the transitional phase (catagen) is marked by the cessation ofmitosis and lasts from two to three weeks; and(c) the resting phase (telogen) in which the hair is retained within thescalp for up to 12 weeks, until it is displaced by new follicular growthfrom the scalp below.

In humans, this growth cycle is not synchronized. An individual willhave thousands of follicles in each of these three phases. However, mostof the hair follicles will be in the anagen phase. In healthy youngadults, the anagen to telogen ratio can be as high as 9 to 1. Inindividuals with alopecia, this ratio is reduced to as low as 2:1.

Androgenetic alopecia arises from activation of an inherited sensitivityto circulating androgenic hormones. It is the most common type ofalopecia. It affects both men (50%) and women (30%), primarily ofCaucasian origin. Gradual changes in the width and length of the hairshaft are experienced over time and with increasing age, prematurely insome. Terminal hair is gradually converted to short, wispy, colorlessvellus hair. As a consequence, men in there 20's and women in their 30'sand 40's begin to notice their hair becoming finer and shorter. Inmales, most of the hair loss occurs at the crown of the head. Femalesexperience a thinning over their entire scalp. As discussed above, theanagen to telogen ratio is reduced significantly, resulting in less hairgrowth.

Minoxidil, a potassium channel opener, promotes hair growth. Minoxidilis available commercially in the United States under the trademark,Rogaine®. While the exact mechanism of action of minoxidil is unknown,its impact on the hair growth cycle is well documented. Minoxidilpromotes the growth of the hair follicle and increase the period of timethat the hair follicle is in the anagen phase (i.e. increases the anagento telogen ratio).

While minoxidil promotes hair growth, the cosmetic efficacy of thisgrowth can vary widely. For example, Roenigk reported the results of aclinical trial involving 83 males who used a topical solution of 3%minoxidil for a period of 19 months. Hair growth occurred in 55% of thesubjects. However, only 20% of the subjects considered the growth to becosmetically relevant. (Clin. Res., 33, No. 4, 914A, 1985). Tostireported cosmetically acceptable re-growth in 18.1% of his subjects.(Dermatologica, 173, No. 3, 136-138, 1986). Thus, the need exists in theart for compounds having the ability produce higher rates ofcosmetically acceptable hair growth in patients with alopecia.

SUMMARY OF THE INVENTION

In accordance with the present invention, a new class of4-cyano-phenoxy-alkyl carboxyl derivatives has been discovered. Thesecompounds, their salts, solvates, and prodrugs thereof, may berepresented by Formula I below:

-   -   wherein;    -   a) X¹ is represented by cyano, halogen or haloalkyl,    -   b) R¹ and R² are each independently represented by hydrogen or        (C₁-C₆) alkyl, optionally substituted,    -   c) Alk¹ is represented by a C₁-C₂ linear alkylene group, in        which up to two hydrogen atoms are optionally replaced by a        substituent selected from the group consisting of C₁-C₆ alkyl        optionally substituted, halogen, hydroxy, thiol, and cyano,    -   d) n is represented by the integer 0 or 1,    -   e) Y is represented by NX²X³ or O—X³,    -   f) X² is represented by hydrogen or (C₁-C₆) alkyl optionally        substituted,    -   g) X³ is represented by,        -   i) hydrogen,        -   ii) (C₁-C₁₂)alkyl, optionally substituted,        -   iii) (C₂-C₁₂)alkenyl, optionally substituted,        -   iv) (C₂-C₁₂)alkynyl, optionally substituted,        -   v) (C₃-C₁₀)cycloalkyl, optionally substituted,        -   vi) (C₃-C₁₀) cycloalkyl(C₁-C₆)alkyl, in which the alkyl and            cycloalkyl moieties may each be optionally substituted,        -   vii) (C₆-C₁₀)aryl, optionally substituted,        -   viii) (C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and aryl            moieties may each be optionally substituted,        -   ix) —(CH₂)-(Alk²)_(q)-C(O)R³, in which Alk² is represented            by a (C₁-C₈) linear alkylene group, in which up to eight            hydrogen atoms may optionally be replaced by a substituent,            selected from the group consisting of (C₁-C₆) alkyl            optionally substituted, (C₁-C₆) alkoxy, halogen, hydroxy,            thiol, cyano, and NR⁸R⁹ in which R⁸ and R⁹ are each            independently represented by hydrogen or (C₁-C₆) alkyl, q is            the integer 0 or 1, R³ is represented by hydrogen,            (C₁-C₁₂)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl, in            which the alkyl and aryl moieties may each be optionally            substituted,        -   x) —(CH₂)-(Alk²)_(q)-C(O)—O—R⁴, in which Alk² and q, are as            defined above, and R⁴ is represented by hydrogen,            (C₁-C₁₂)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl, in            which the alkyl and aryl moieties may be optionally            substituted,        -   xi) —(CH₂)-(Alk²)_(q)-C(O)—NR⁵R⁶ in which Alk² and q are as            described above, and R⁵ and R⁶ are each independently            represented by hydrogen, (C₁-C₁₂)alkyl, (C₆-C₁₀)aryl, or            (C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and aryl            moieties may be optionally substituted,        -   xii) —(CH₂)-(Alk²)_(q)-Y—R⁷, in which Alk² and q are as            defined above, Y is O or S, and R⁷ is selected from the            group consisting of hydrogen, (C₁-C₁₂)alkyl, (C₆-C₁₀)aryl,            or (C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and aryl            moieties may be optionally substituted,        -   xiii) heteroaryl, optionally substituted,        -   xiv) heteroaryl(C₁-C₆)alkyl, in which the heteroaryl and            alkyl moieties may each be optionally substituted,        -   xv) heterocyclic, optionally substituted,        -   xvi) heterocyclic(C₁-C₆)alkyl, in which the alkyl and            heterocyclic moieties may each be substituted, or,    -   h) for those compounds in which Y is N, X² and X³, together with        the adjacent nitrogen atom, may form a heterocyclic ring, which        may optionally be substituted.

The compounds of Formula I are androgen receptor modulators. Thecompounds have affinity for the androgen receptor and will cause abiological effect by binding to the receptor. Typically, the compoundswill act as antagonists. In selected embodiments they will act aspartial agonists, full agonists, or tissue selective agonists. Asandrogen receptor modulators, the compounds can be used to treat, oralleviate, conditions associated with inappropriate activation of theandrogen receptor. Examples of such conditions for antagonists include,but are not limited to, acne, excess sebum secretion, androgenicalopecia, hormone dependant cancers such as prostrate cancer, andhirsutism. Those compounds that are partial agonists, or full agonists,can be used to treat osteoporosis, hypogonadism, anemia, or to stimulateincreases in muscle mass, especially in wasting diseases.

The invention is also directed to pharmaceutical compositions containingat least one of the compounds, in an amount effective to modulateactivation of the androgen receptor. In a further embodiment, theinvention is directed to an article of manufacture containing at leastone of the compounds packaged for retail distribution, in associationwith instructions advising the consumer on how to use the compound toalleviate a condition associated with inappropriate activation of theandrogen receptor. An additional embodiment is directed to the use of acompound as a diagnostic agent to detect inappropriate activation of theandrogen receptor.

In a further embodiment, the compounds are used topically to induceand/or stimulate hair growth and/or to slow down hair loss. Thecompounds may also be used topically in the treatment of excess sebumand/or of acne.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the hair growth observed in a group of test animals.

DETAILED DESCRIPTION OF THE INVENTION

The headings within this document are only being utilized expedite itsreview by the reader. They should not be construed as limiting theinvention or claims in any manner.

Definitions and Exemplification

As used throughout this application, including the claims, the followingterms have the meanings defined below, unless specifically indicatedotherwise. The plural and singular should be treated as interchangeable,other than the indication of number:

-   -   a. “halogen” refers to a chlorine, fluorine or bromine atom.    -   b. “C₁-C₆ alkyl” refers to a branched or straight chained alkyl        group containing from 1 to 6 carbon atoms, such as methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, etc.    -   c. “C₁-C₆ alkyl, optionally substituted” refers to a branched or        straight chained alkyl group containing from 1 to 6 carbon        atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,        isobutyl, pentyl, etc. Such an alkyl group may be optionally        substituted, in which up to 6 hydrogen atoms are replaced by a        substituent selected from the group consisting of halogen,        hydroxy, thiol, cyano, and NR⁸R⁹, in which R⁸ and R⁹ are each        independently represented by hydrogen or (C₁-C₆) alkyl.    -   d. “haloalkyl” refers to a branched or straight chained alkyl        group containing from 1 to 6 carbon atoms, in which at least one        hydrogen atom is replaced with a halogen (i.e. C₁-C₆ haloalkyl).        Examples of suitable haloalkyl's include chloromethyl,        difluoromethyl, trifluoromethyl, 1-fluoro-2-chloro-ethyl,        5-fluoro-hexyl, 3-difluoro-isopropyl, 3-chloro-isobutyl, etc.    -   e. “linear alkylene group containing from 1 to 2 carbon atoms”        (i.e. “C₁-C₂ linear alkylene group”) refers to an alkylene group        containing 1 or 2 carbon atoms and serving as a linking group        within the molecule (i.e. no terminal —CH₃ function). Examples        of such alkyl groups include —CH₂—, or —CH₂—CH₂.    -   f. “linear alkylene group containing from 1 to 8 carbon atoms”        (i.e. “C₁-C₈ linear alkylene group”) refers to an alky group        containing from 1 to 8 carbon atoms serving as a linking group        within the molecule (i.e. no terminal —CH₃ function). Examples        of such alkyl groups include —CH₂—, —CH₂—(CH₂)₄—CH₂—,        —CH₂—(CH₂)₆—CH₂, —CH₂—CH₂—CH₂—, —CH₂—(CH₂)₂—CH₂—, etc.    -   g. “(C₁-C₂)alkyl substituted with one or more halogen atoms”        refers to a straight chained alkyl group containing 1 or 2        carbon atoms, i.e., methyl or ethyl in which at least one        hydrogen atom is replaced with a halogen (i.e. for example        trifluoromethyl, dichloromethyl, etc.).    -   h. “(C₁-C₂)alkoxy substituted with one or more halogen atoms”        refers to a straight chained alkoxy group containing 1 or 2        carbon atoms, i.e., methoxy or ethoxy in which at least one        hydrogen atom is replaced with a halogen (i.e. for example        trifluoromethoxy, difluoromethoxy, etc.)    -   i. “heteroatom” includes oxygen, nitrogen, and sulfur.    -   j. “C₁-C₆ alkoxy” refers to a straight or branched chain alkoxy        group containing from 1 to 6 carbon atoms, such as methoxy,        ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentoxy,        etc.    -   k. “C₁-C₁₂ alkyl” refers to a branched or straight chained alkyl        group containing from 1 to 12 carbon atoms, such as methyl,        ethyl, n-propyl, isopropyl, n-butyl, isobutyl, hexyl, octyl,        decyl, etc. Such an alkyl group may be optionally substituted,        in which up to 8 hydrogen atoms are replaced by a substituent        selected from the group consisting of halogen, haloalkyl,        hydroxy, thiol, cyano, and —NR⁸R⁹, in which R⁸ and R⁹ are as        defined above.    -   l. “C₂-C₁₂ alkenyl” refers to a straight-chain or branched-chain        hydrocarbon radical containing from 2 to 12 carbon atoms and 1,        or more, carbon-carbon double bonds. Examples of alkenyl        radicals include ethenyl, propenyl, 1,4-butadienyl, 1-hexenyl,        1,3-octadienyl and the like. Such an alkenyl group may be        optionally substituted, in which up to 8 hydrogen atoms are        replaced by a substituent selected from the group consisting of        halogen, haloalkyl, hydroxy, thiol, cyano, and —NR⁸R⁹, in which        R⁸ and R⁹ are as defined above.    -   m. “C₂-C₁₂ alkynyl” refers to a straight-chain or branched-chain        hydrocarbon radical containing from 2 to 12 carbon atoms and        having 1, or more, carbon-carbon triple bonds. Examples of        alkynyl radicals include ethynyl, propynyl, butynyl, octynyl,        and the like. Such an alkynyl group may be optionally        substituted, in which up to 8 hydrogen atoms are replaced by a        substituent selected from the group consisting of halogen,        hydroxy, haloalkyl, thiol, cyano, and —NR⁸R⁹, in which R⁸ and R⁹        are as defined above.    -   n. “(C₆-C₁₀)aryl” means a cyclic, aromatic hydrocarbon        containing from 6 to 10 carbon atoms. Examples of aryl groups        include phenyl, naphthyl and biphenyl. Such an aryl moiety may        be optionally substituted with up to 4 non-hydrogen        substituents, each substituent is independently selected from        the group consisting of halogen, cyano, hydroxy, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₂)alkyl substituted with one or more        halogens, (C₁-C₂)alkoxy substituted with one or more halogens,        SR⁸ and NR⁸R⁹. R⁸ and R⁹ are each independently represented by        C₁-C₆ alkyl or hydrogen. These substituents may be the same or        different and may be located at any position of the ring, that        is chemically permissible.    -   o. “heteroaryl” refers to an aromatic ring having one, or more,        heteroatoms selected from oxygen, nitrogen and sulfur. More        specifically, it refers to a 5- or 6-, membered ring containing        1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1        nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2        nitrogen atoms and 1 oxygen atom; or 2 nitrogen atoms and 1        sulfur atom. The 5-membered ring has 2 double bonds and the        6-membered ring has 3 double bonds. The term heteroaryl also        includes bicyclic groups in which the heteroaryl ring is fused        to a benzene ring, heterocyclic ring, a cycloalkyl ring, or        another heteroaryl ring. Examples of such heteroaryl ring        systems include, but are not limited to, pyrrolyl, furanyl,        thienyl, imidazolyl, oxazolyl, indolyl, thiazolyl, pyrazolyl,        pyridinyl, pyrimidinyl, purinyl, quinolinyl, benzofuran and        isoquinolinyl.    -   p. “heteroaryl, optionally substituted,” refers to a heteroaryl        moiety as defined immediately above, in which up to 4 carbon        atoms of the heteroaryl moiety may be substituted with a        substituent, each substituent is independently selected from the        group consisting of halogen, cyano, hydroxy, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₂)alkyl substituted with one or more        halogens, (C₁-C₂)alkoxy substituted with one or more halogens,        SR⁸, and NR⁸R⁹, in which R⁸ and R⁹ are as defined above.    -   q. “heterocycle” or “heterocyclic ring” refers to any 3- or        4-membered ring containing a heteroatom selected from oxygen,        nitrogen and sulfur; or a 5-, 6-, 7-, 8-, 9-, or 10-membered        ring containing 1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1        sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1        oxygen atom; 2 oxygen atoms in non-adjacent positions; 1 oxygen        and 1 sulfur atom in non-adjacent positions; or 2 sulfur atoms        in non-adjacent positions. The 5-membered ring has 0 to 1 double        bonds, the 6- and 7-membered rings have 0 to 2 double bonds, and        the 8, 9, or 10 membered rings may have 0, 1, 2, or 3 double        bonds. The term “heterocyclic” also includes bicyclic groups in        which any of the above heterocyclic rings is fused to a benzene        ring, a cyclohexane or cyclopentane ring or another heterocyclic        ring (for example, indolyl, quinolyl, isoquinolyl,        tetrahydroquinolyl, benzofuryl, dihydrobenzofuryl or        benzothienyl and the like). Heterocyclics include: pyrrolidinyl,        tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl,        piperazinyl, azepane, azocane, morpholinyl, isochroamyl and        quinolinyl.    -   r. “heterocyclic, optionally substituted” refers to a        heterocyclic moiety as defined immediately above, in which up to        4 carbon atoms of the heterocycle moiety may be substituted with        a substituent, each substituent is independently selected from        the group consisting of halogen, cyano, hydroxy, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₂)alkyl substituted with one or more        halogens, (C₁-C₂)alkoxy substituted with one or more halogens,        SR⁸, and NR⁸R⁹, in which R⁸ and R⁹ are as defined above. Any        nitrogen atom within such a heterocyclic ring may optionally be        substituted with (C₁-C₆) alkyl, if such substitution is        chemically permissible.    -   s. “C₃-C₁₀ cycloalkyl” refers to a saturated or partially        saturated monocyclic, bicyclic or tricyclic alkyl radical        wherein each cyclic moiety has 3 to 10 carbon atoms. Examples of        cycloalkyl radicals include cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cyclooctyl, and the like. Such a        cycloalkyl group may be optionally substituted, in which up to 4        hydrogen atoms are replaced by a substituent selected from the        group consisting of halogen, cyano, hydroxy, (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, (C₁-C₂)alkyl substituted with one or more        halogens, (C₁-C₂)alkoxy substituted with one or more halogens,        SR⁸, and NR⁸R⁹, in which R⁸ and R⁹ are as defined above.    -   t. “androgen” refers to testosterone and its precursors and        metabolites, and 5-alpha reduced androgens, including but not        limited to dihydrotestosterone. Androgen refers to androgens        from the testis, adrenal gland, and ovaries, as well as all        forms of natural, synthetic and substituted or modified        androgens.    -   u. “pharmaceutically acceptable” means suitable for use in        mammals.    -   v. “salts” is intended to refer pharmaceutically acceptable        salts and to salts suitable for use industrial processes, such        as the preparation of the compound.    -   w. “pharmaceutically acceptable salts” is intended to refer to        either pharmaceutically acceptable acid addition salts” or        “pharmaceutically acceptable basic addition salts” depending        upon actual structure of the compound.    -   x. “pharmaceutically acceptable acid addition salts” is intended        to apply to any non-toxic organic or inorganic acid addition        salt of the base compounds represented by Formula I or any of        its intermediates. Illustrative inorganic acids which form        suitable salts include hydrochloric, hydrobromic, sulphuric, and        phosphoric acid and acid metal salts such as sodium monohydrogen        orthophosphate, and potassium hydrogen sulfate. Illustrative        organic acids, which form suitable salts include the mono-, di-,        and tricarboxylic acids. Illustrative of such acids are for        example, acetic, glycolic, lactic, pyruvic, malonic, succinic,        glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,        hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic,        salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and        sulfonic acids such as methane sulfonic acid and 2-hydroxyethane        sulfonic acid. Such salts can exist in either a hydrated or        substantially anhydrous form. In general, the acid addition        salts of these compounds are soluble in water and various        hydrophilic organic solvents, and which in comparison to their        free base forms, generally demonstrate higher melting points.    -   y. “pharmaceutically acceptable basic addition salts” is        intended to apply to any non-toxic organic or inorganic basic        addition salts of the compounds represented by Formula I, or any        of its intermediates. Illustrative bases which form suitable        salts include alkali metal or alkaline-earth metal hydroxides        such as sodium, potassium, calcium, magnesium, or barium        hydroxides; ammonia, and aliphatic, alicyclic, or aromatic        organic amines such as methylamine, dimethylamine,        trimethylamine, and picoline.    -   z. “prodrug” refers to compounds that are rapidly transformed in        vivo to yield the parent compound of the above formulas, for        example, by hydrolysis in blood. A thorough discussion is        provided in T. Higuchi and V. Stella, “Pro-drugs as Novel        Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and        in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,        American Pharmaceutical Association and Pergamon Press, 1987,        both of which are incorporated herein by reference.    -   aa. “compound of Formula I”, “compounds of the invention”, and        “compounds” are used interchangeably throughout the application        and should be treated as synonyms.    -   bb. “patient” refers to warm blooded animals such as, for        example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs,        monkeys, chimpanzees, and humans.    -   cc. “treat” refers to the ability of the compounds to either        relieve, alleviate, or slow the progression of the patient's        disease (or condition) or any tissue damage associated with the        disease.

Some of the compounds of Formula I will exist as optical isomers. Anyreference in this application to one of the compounds represented byFormula I is meant to encompass either a specific optical isomer or amixture of optical isomers (unless it is expressly excluded). Thespecific optical isomers can be separated and recovered by techniquesknown in the art such as chromatography on chiral stationary phases orresolution via chiral salt formation and subsequent separation byselective crystallization. Alternatively utilization of a specificoptical isomer as the starting material will produce the correspondingisomer as the final product.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention. The compounds may also exist in one or morecrystalline states, i.e. polymorphs, or they may exist as amorphoussolids. All such forms are encompassed by the claims.

All of the compounds of Formula I contain a phenyl ring. To furtherexemplify the invention, the numbering system for this ring and itssubstitution pattern is shown below:

Position 4 of this phenyl ring is substituted with a cyano moiety asdepicted above. Position 1 is substituted with an oxygen atom forming anether moiety. The phenyl ring will be further substituted, as depictedby X¹, at position 2 or 3, with a halogen atom a haloalkyl moiety, or acyano function. Typically, this halogen, cyano or haloalkyl moiety willbe at the 3-position. More typically it will be trifluoromethyl locatedat the 3-position of the phenyl ring.

As noted above, position 1 of the phenyl ring is substituted with theether moiety, —CR¹R²-(Alk¹)_(n)-C(O)—Y. Typically, one of R¹ or R² willbe represented by C₁-C₆ alkyl, which may be optionally substituted. Theother of R¹ or R² may be represented by hydrogen or C₁-C₆ alkyl,optionally substituted. More typically, one of R¹ or R² is unsubstitutedC₁-C₆ alkyl, and the other is a hydrogen atom. More typically one of R¹or R² is isobutyl, or n-propyl, and the other is a hydrogen atom.

Alk¹, when present, will be represented by a methylene orethylene-bridging group. Up to two hydrogen atoms of this alkylenebridging group may be replaced with one of the substituents definedabove. Any single carbon atom of Alk¹ may be unsubstituted,monosubstituted, or disubstituted. These carbon atoms may be substitutedwith the same substituent or differing substituents. Typically, Alk¹will be absent.

Y, along with the adjacent carbonyl group, may form an amide, an ester,a carboxylic acid, or a carboxylate anion. Typically, Y is a nitrogenatom. X² and X³ may each be represented by one of the substituentslisted above. Alternatively, X² and X³ along with the nitrogen atom mayform a heterocyclic ring, which may be further substituted as describedabove.

More specific embodiments of the invention include those compound inwhich:

X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl or propyl, R² is hydrogen, n is 0, Y is representedby —NX²X³;X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl or propyl, R² is hydrogen, n is 0, Y is representedby O,X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl, R² is hydrogen, n is 0, Y is represented by —NX²X³in which X² is represented by hydrogen and X³ is as defined above,X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl, R² is hydrogen, n is 0, Y is represented by —NX²X³in which X² is represented by hydrogen and X³ is(C₆-C₁₀)aryl(C₁-C₆alky), in which the aryl moiety is phenyl, and thealkyl moiety is methyl, or ethyl;X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl or propyl, R² is hydrogen, n is 0, Y is representedby —NX²X³ in which X² is represented by hydrogen and X³ is(C₆-C₁₀)aryl(C₁-C₆alky), in which the aryl moiety is phenyl, optionallysubstituted with at least one substituent selected from the groupconsisting of methoxy, ethoxy, hydroxy, methyl, and the alkyl moiety ismethyl or ethyl;X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl or propyl, R² is hydrogen, n is 0, Y is representedby —NX²X³ in which X² is represented by hydrogen and X³ is C₁-C₁₂ alkyl,more specifically isopropyl, isobutyl;X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl or propyl, R² is hydrogen, n is 0, Y is representedby —NX²X³ in which X² is represented by hydrogen and X³ isheteroaryl(C₁-C₆alky), in which the heteroaryl moiety is optionallysubstituted, and the alkyl moiety is methyl or ethyl;X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl or propyl, R² is hydrogen, n is 0, Y is representedby —NX²X³ in which X² is represented by hydrogen and X³ isheteroaryl(C₁-C₆alky), in which the heteroaryl moiety is pyridine,furan, thiophene, indolyl, and the alkyl moiety is methyl or ethyl;X¹ is represented by CF₃ and is located at the 3-position of the phenylring, R¹ is isobutyl or propyl, R² is hydrogen, n is 0, Y is representedby —NX²X³ in which X² is represented by hydrogen and X³ is(C₃-C₁₀)cycloalkyl(C₁-C₆alky).

More specific examples of compounds encompassed by Formula I include:

-   a) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid,-   b) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    benzylamide,-   c) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid,-   d) 2-(4-cyano-3-chloro-phenoxy)-pentanoic acid,-   e) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    isopropylamide,-   f) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    ethylamide,-   g) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid benzylamide,-   h) 2-(4-cyano-3-fluoro-phenoxy)-hexanoic acid benzylamide,-   i) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid ethylamide,-   j) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    [1-(4-hydroxy-phenyl)-ethyl]-amide,-   k) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    cyclopropylmethyl-amide,-   l) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    cyclohexylmethyl-amide,-   m) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    cyclopropylethyl-amide,-   n) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    cyclohexylethyl-amide,-   o) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    isobutyl-amide,-   p) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    hexyl-amide,-   q) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    [2-(4-methoxy-phenyl)-ethyl]-amide,-   r) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    [2-(4-fluoro-phenyl)-ethyl]-amide,-   s) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-phenoxy-ethyl)-amide,-   t) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (furan-2-yl-methyl)-amide,-   u) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-piperidino-methyl)-amide,-   v) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (thiophen-2-yl-methyl)-amide,-   w) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (pyrrol-2-yl-methyl)-amide,-   x) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (1-thiophen-2-yl-ethyl)-amide,-   y) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (1-methyl-2-thiophen-3-yl-ethyl)-amide,-   z) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (1-pyridin-3-yl-ethyl)-amide,-   aa) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (pyridin-4-yl-methyl)-amide,-   bb) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (1-thiophen-2-yl-ethyl)-amide,-   cc) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (1-methyl-2-thiophen-3-yl-ethyl)-amide,-   dd) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (pyridin-3-yl-methyl)-amide,-   ee) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (indol-3-yl-methyl)-amide,-   ff) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-methyl-pyridin-2-yl-methyl)-amide,-   gg) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-methylsulfanyl-propyl)-amide,-   hh) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-benzyl-sulfanyl-propyl)-amide,-   ii) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-methyl-butyl)-amide,-   jj) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3,3-diethoxy-propyl)-amide,-   kk) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (benzo[1,3]dioxol-5-yl-methyl)-amide,-   ll) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2,3-dihydro-benzofuran-5-yl-methyl)-amide,-   mm) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (benzo[1,2,5]thiadiazol-5-yl-methyl)-amide,-   nn) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (isochroman-3-yl-methyl)-amide,-   oo) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-methylsulfanyl-propyl)-amide,-   pp) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (benzo[1,3]dioxol-5-yl-methyl)-amide,-   qq) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (2,3-dihydro-benzofuran-5-yl-methyl)-amide,-   rr) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (2,3-dihydro-benzofuran-2-yl-methyl)-amide,-   ss) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (benzo[1,2,5]thiadiazo-5-yl-methyl)-amide,-   tt) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (isochroman-3-yl-methyl)-amide,-   uu) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-3-methoxy-benzylamide,-   vv) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-3-methoxy-4-trifluoromethyl-benzylamide,-   ww) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    [2-(4-methoxy-phenyl)-ethyl]amide,-   xx) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-2-methoxy-benzylamide,-   yy) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-hexanoic    acid-2-methoxy-benzylamide,-   zz) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-2-ethoxy-benzylamide,-   aaa) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-3-methyl-benzylamide,-   bbb) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-2-methyl-benzylamide,-   ccc) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-4-methoxy-benzylamide,-   ddd) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-3-methoxy-benzylamide,-   eee) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-2-methoxy-benzylamide,-   fff) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-2-ethoxy-benzylamide,-   ggg) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-3-methyl-benzylamide,-   hhh) 2-(4-cyano-3-trifluoromethyl-phenoxy)-hexanoic acid-phenylhexyl    amide,-   iii) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-2-methyl-benzylamide,-   jjj) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-2,4-dimethyl-benzylamide,-   kkk) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-4-methoxy-benzylamide,-   lll) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-(2-p-tolyl-ethyl)-amide,-   mmm) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-[2-(2-methoxy-phenyl)-ethyl]-amide,-   nnn) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-(2-m-tolyl-ethyl)-amide,-   ooo) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-(2-p-tolyl-ethyl)-amide,-   ppp) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-[2-(2-methoxy-phenyl)-ethyl]-amide,-   qqq) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-(2-m-tolyl-ethyl)-amide,-   rrr) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-(2-phenoxy-propyl)-amide,-   sss) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-(phenoxy-hexyl)-amide,-   ttt) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    indan-1-yl-amide,-   uuu) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-(2-phenoxy-propyl)-amide,-   vvv) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-(2-phenoxy-ethyl)-amide,-   www) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    indan-1-yl-amide,-   xxx) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-[2-(3-methoxy-phenyl)-ethyl]-amide,-   yyy) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    [2-(1H-indol-3-yl)-ethyl]amide,-   zzz) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2H-imidazo[1,2-a]pyridin-3-yl)-methyl)amide,-   aaaa) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-[2-(4-hydroxy-phenyl)-ethyl]-amide,-   bbbb) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-(3-pyridin-3-yl-propyl)-amide,-   cccc) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    benzyl-isopropyl-amide,-   dddd) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    benzyl-methyl-amide,-   eeee) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    benzyl-1-hydroxy-pentyl-amide,-   ffff) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-[2-(3-methoxy-phenyl)-ethyl]-amide,-   gggg) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    [2-(1H-indol-3-yl)-ethyl]amide,-   hhhh) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic    acid-[2-(4-hydroxy-phenyl)-ethyl]-amide,-   iiii) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    benzyl-isopropyl-amide,-   jjjj) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-dimethylamino-2-phenyl-ethyl)-amide,-   kkkk) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    [1-(4-hydroxy-phenyl)-ethyl]-amide,-   llll) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    4-isopropyl-benzylamide,-   mmmm) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-3-methoxy-benzylamide,-   nnnn) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-(6-methoxy-pyridin-3-yl-methyl)-amide,-   oooo) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-4-methoxy-benzylamide,-   pppp) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-3,4-dihydroxy-benzylamide,-   qqqq) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-(2-methyl-butyl)-amide,-   rrrr) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-piperidine-amide,-   ssss) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-pyrrolidine-amide-   tttt) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-pyrrolidine-amide-   uuuu) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid-piperazine-amide-   vvvv) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-methyl-pyridin-3-yl-methyl)-amide,-   wwww) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (naphthalene-1-yl-methyl)-amide,-   xxxx) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-hydroxy-4-methyl-phenyl)-amide,-   yyyy) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-hydroxy-ethyl)-isopropyl-amide,-   zzzz) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-methylsulfanyl-propyl)-amide,-   aaaaa) 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-propoxy-ethyl)-amide,-   bbbbb) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (1-methoxymethyl-propyl)-amide,-   ccccc) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-methylsulfanyl-ethyl)-amide,-   ddddd)-2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-hydroxy-2-methyl-phenyl)-amide,-   eeeee) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-propoxy-propyl)-amide,-   fffff) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    ethyl(2-methoxy-ethyl)-amide,-   ggggg) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (2-methoxy-phenyl)-amide,-   hhhhh) 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid    (3-hydroxy-4-methyl-phenyl)-amide,-   iiiii) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (3-methylsulfanyl-propyl)-amide,-   jjjjj) 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    (2-methylsulfanyl-ethyl)-amide,-   kkkkk) 2-(4-cyano-3-trifluoromethyl-phenoxy)-hexanoic acid    benzylamide,-   lllll)    N-benzyl-2-(4-cyano-3-trifluoromethyl-phenoxy)-3-methyl-butyramide,-   mmmmm) N-benzyl-2-(4-cyano-3-trifluoromethyl-phenoxy)-butyramide,-   nnnnn) N-benzyl-2-(4-cyano-3-trifluoromethyl-phenoxy)-propylamide,-   ooooo) (R)-2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic    acid benzylamide, and-   ppppp) (R)-2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid    benzylamide.

Synthesis

The compounds of Formula I can be prepared by methods known in the art.One method for preparing these compounds is described below in ReactionSchemes I, II, and III. Reaction Scheme I describes the synthesis of acompound of Formula I in which Y is OH, i.e. a carboxylic acid. Ifdesired, this acid may then be converted into an amide as described inReaction Scheme II. Reaction Scheme III describes one method forconverting the acid into an ester.

The initial step is to carry out a nucleophilic substitution reactionwith a benzonitrile as described by structure 1 and an alcohol asdescribed by structure 2. In the alcohol of structure of 2, R¹, R², andAlk¹ should be represented by the same substituent as is desired in thefinal product. Pg represents a suitable protecting group. Examples ofsuch protecting groups include isopropyl, benzyl, etc. The reader'sattention is directed to T. W. Greene, Protective Groups in OrganicSynthesis, John Wiley & Sons, New York, 1991, for further suggestionsregarding suitable protecting groups. The alcohols of structure 2 areknown in the art can be prepared as described in Tetrahedron Letters,1998, 29(20), 2453-2454.

The other starting material is a 4-fluoro-benzonitrile as depicted bystructure 1. X¹ should be represented by the same substituent as desiredin the final product. These benzonitriles are known in the art and maybe synthesized as described by Japanese Patent Application Number01097937.

The nucleophilic substitution depicted above may be carried out as isknown in the art. The alcohol of structure 2 is contacted with a slightexcess of a base, such as sodium hydride, to produce an alkoxide ion.The reaction is carried out in an aprotic solvent, such astetrahydrofuran, under an inert atmosphere (typically nitrogen) at atemperature of about 0° C. The alcohol is stirred with the base for aperiod of time ranging from 5 to 60 minutes.

One equivalent of the 4-fluoro-benzonitrile of structure 1 is then addedto the reaction and the reactants are stirred for a sufficient period oftime to allow the alkoxide ion to displace the fluorine from thebenzonitrile. This typically takes from 30 minutes to 24 hours. Thereaction is typically allowed to warm to room temperature.

The resulting product, a compound of structure 3, can be recovered byextraction, evaporation, or other techniques known in the art. It maythen optionally be purified by chromatography, recrystallization,distillation, or other techniques known in the art. Alternatively, thecompound of structure 3 may be utilized directly in the deprotectionreaction described above, without subsequent recovery or purification.

The deprotection reaction is carried out as is known in the art. Thecompound of structure 3 is contacted with an excess of a weak base, suchas lithium hydroxide, in a solvent such as an admixture oftetrahydrofuran and water. The reactants are heated to reflux for asufficient period of time to remove the protecting group, which istypically accomplished in a period of time ranging from 5 minutes to 24hours. The reaction is then cooled and the free acid is generatedintroducing a strong acid into the reaction, such as hydrochloric acid,sulfuric acid, etc. The desired compound of Formula I, in which Y is OH,can be recovered by extraction, evaporation, or other techniques knownin the art. It may then optionally be purified by chromatography,recrystallization, distillation, or other techniques known in the art.

If the desired compound of Formula I is an amide (i.e. Y is NX²X³), thenit may be generated as depicted in Reaction Scheme II:

The free acid of Formula I may be converted to an amide using a couplingreaction as is known in the art. One of the reactants is the amine asdescribed by structure 4. X² and X³ will be represented by the samesubstituent as desired in the final product of Formula I. These aminesare known in the art and can be prepared as described in Journal of theAmerican Chemical Society (1927), 49, 2908-2914.

The coupling reaction may be carried out as is known in the art. Suchreactions are described in Journal of the American Chemical Society,109(10), 3087-3091, 1987. Typically, the free acid of Formula I iscontacted with an excess of the amine of structure 4 in the presence ofan weak organic base such as diisopropyl ethyl amine, in a solvent suchas DMF(N,N-dimethylformamide). Other potential bases includeN-methylmorpholine, carbodiimide, etc. A coupling agent is typicallyadded to the reaction. Examples of such coupling agents include1-hydroxybenzotriazole “HOBT”, 1-H-Benzotriazolium “HBTU”, and(1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. Thereaction is typically carried out at room temperature for a period oftime ranging from 5 minutes to 24 hours. The desired product of FormulaI may be recovered by extraction, evaporation, or other techniques knownin the art. It may then optionally be purified by chromatography,recrystallization, distillation, or other techniques known in the art.

If the desired product of Formula I is an ester, it may be synthesizedas described in Reaction Scheme III below:

The free acid of Formula I is transformed into the acid chloride ofstructure 5, as known in the art. Please refer to Tetrahedron Letters(1986), 27(49), 5997-6000 for further details regarding the preparationof acid chlorides

Typically the free acid is contacted with an excess of thionyl chloridein an organic solvent such as THF. The acid chloride of structure 5 maybe recovered by distillation as is known in the art.

The acid chloride of structure 5 is converted into an ester as is knownin the art. The acid chloride is contacted with an alcohol as describedby structure 6, in which X³ is represented by the same substituent as isdesired in the final product. These alcohols are known in the art

The esterification is carried out by contacting the acid chloride withthe alcohol of structure 6 in the presence of a mineral acid such ashydrochloric acid, sulfuric acid, etc., in an organic solvent such asacetonitrile under elevated temperatures. Such reactions are describedin Tetrahedron Letters, 43(47), 8603-8606; 2002

As is readily apparent to one skilled in the art, carboxylic acids canbe converted into amides and esters by a number of techniques. Thereader's attention is directed to Journal of the American ChemicalSociety, 109(10), 3087-3091, 1987, for a brief description of suchreactions. These alternative reactions may also be used to produce theamides and ester of Formula I.

As would be appreciated by those skilled in the art, some of the methodsuseful for the preparation of such compounds, as discussed above, mayrequire protection of a particular functionality, e.g., to preventinterference by such functionality in reactions at other sites withinthe molecule or to preserve the integrity of such functionality. Theneed for, and type of, such protection is readily determined by oneskilled in the art, and will vary depending on, for example, the natureof the functionality and the conditions of the selected preparationmethod. See, e.g., T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, 1991.

Some of the compounds of this invention are acidic and they form a saltwith a pharmaceutically acceptable cation. Some of the compounds of thisinvention are basic and they form a salt with a pharmaceuticallyacceptable anion. All such salts are within the scope of this inventionand they can be prepared by conventional methods such as combining theacidic and basic entities, usually in a stoichiometric ratio, in eitheran aqueous, non-aqueous or partially aqueous medium, as appropriate. Thesalts are recovered either by filtration, by precipitation with anon-solvent followed by filtration, by evaporation of the solvent, or,in the case of aqueous solutions, by lyophilization, as appropriate. Thecompounds are obtained in crystalline form according to procedures knownin the art, such as by dissolution in an appropriate solvent(s) such asethanol, hexanes or water/ethanol mixtures.

Medical and Cosmetic Uses

The compounds of Formula I are androgen receptor modulators. They can beused to alleviate conditions associated with inappropriate activation ofthe androgen receptor. Compounds acting as androgen antagonists may beused to treat, or alleviate, hormone dependent cancers such as prostatecarcinomas, benign hyperplasia of the prostate, acne, hirsutism, excesssebum, alopecia, hypertrichosis, precocious puberty, prostamegaly,virilization, and polycystic ovary syndrome. Compounds acting as partialagonists, or full agonists, may be used to treat, or alleviate, malehypogonadism, male sexual dysfunction (impotence, male dysspemtatogenicsterility), abnormal sex differentiation (male hermaphroditism), maledelayed puberty, male infertility, aplastic anemia, hemolytic anemia,sickle cell anemia, idiopathic thrombocytopenic purpura, myelofibrosis,renal anemia, wasting diseases (post operative, malignant tumor, trauma,chronic renal disease, burn or AIDS induced), abatement of pain interminal carcinoma of female genitalia, inoperable breast cancer,mastopathy, endometriosis, female sexual dysfunction, osteoporosis,wound healing and muscle tissue repair.

In order to exhibit the therapeutic properties described above, thecompounds need to be administered in a quantity sufficient to modulateactivation of the androgen receptor. This amount can vary depending uponthe particular disease/condition being treated, the severity of thepatient's disease/condition, the patient, the particular compound beingadministered, the route of administration, and the presence of otherunderlying disease states within the patient, etc. When administeredsystemically, the compounds typically exhibit their effect at a dosagerange of from about 0.1 mg/kg/day to about 100 mg/kg/day for any of thediseases or conditions listed above. Repetitive daily administration maybe desirable and will vary according to the conditions outlined above.

The compounds of the present invention may be administered by a varietyof routes. They may be administered orally. The compounds may also beadministered parenterally (i.e. subcutaneously, intravenously,intramuscularly, intraperitoneally, or intrathecally), rectally, ortopically.

In a typical embodiment, the compounds are administered topically.Topical administration is especially appropriate for hirsutism,alopecia, acne and excess sebum. The dose will vary, but as a generalguideline, the compound will be present in a dermatologically acceptablecarrier in an amount of from about 0.01 to 50 w/w %, and more typicallyfrom about 0.1 to 10 w/w %. The dermatological preparation will beapplied to the affected area from 1 to 4 times daily. “Dermatologicallyacceptable” refers to a carrier which may be applied to the skin orhair, and which will allow the drug to diffuse to the site of action.More specifically, it refers the site where inhibition of activation ofan androgen receptor is desired.

In a further embodiment, the compounds are used topically to relievealopecia, especially androgenic alopecia. Androgens have a profoundeffect on both hair growth and hair loss. In most body sites, such asthe beard and pubic skin, androgens stimulate hair growth by prolongingthe growth phase of the hair cycle (anagen) and increasing folliclesize. Hair growth on the scalp does not require androgens but,paradoxically, androgens are necessary for balding on the scalp ingenetically predisposed individuals (androgenic alopecia) where there isa progressive decline in the duration of anagen and in hair folliclesize. Androgenic alopecia is also common in women where it usuallypresent as a diffuse hair loss rather than showing the patterning seenin men.

While the compounds will most typically be used to alleviate androgenicalopecia, the invention is not limited to this specific condition. Thecompounds may be used to alleviate any type of alopecia. Examples ofnon-androgenic alopecia include alopecia areata, alopecia due toradiotherapy or chemotherapy, scarring alopecia, stress relatedalopecia, etc. As used in this application, “alopecia” refers to partialor complete hair loss on the scalp.

Thus, the compounds can be applied topically to the scalp and hair toprevent, or alleviate balding. Further, the compound can be appliedtopically in order to induce or promote the growth of hair on the scalp.

In a further embodiment of the invention, a compound of Formula I isapplied topically in order to prevent the growth of hair in areas wheresuch hair growth is not desired. One such use will be to alleviatehirsutism. Hirsutism is excessive hair growth in areas that typically donot have hair (i.e. a female face). Such inappropriate hair growthoccurs most commonly in women and is frequently seen at menopause. Thetopical administration of the compounds will alleviate this conditionleading to a reduction, or elimination of this inappropriate, orundesired, hair growth.

The compounds may also be used topically to decrease sebum productionand more specifically to alleviate oily skin. Likewise the compounds canbe used topically to alleviate acne.

In a further embodiment, those compounds acting as partial agonists, orfull agonists, may be used to treat, or alleviate, osteoporosis.Osteoporosis is characterized by bone loss, resulting from an imbalancebetween bone resorption (destruction) and bone formation, which startsin the fourth decade and continues throughout life at the rate of about1-4% per year (Eastell, Treatment of postmenopausal osteoporosis, NewEng. J. Med. 338: 736, 1998). In the United States, there are currentlyabout 20 million people with detectable fractures of the vertebrae dueto osteoporosis. In addition, there are about 250,000 hip fractures peryear due to osteoporosis, associated with a 12%-20% mortality ratewithin the first two years, while 30% of patients require nursing homecare after the fracture and many never become fully ambulatory again. Inpostmenopausal women, estrogen deficiency leads to increased boneresorption resulting in bone loss in the vertebrae of around 5% peryear, immediately following menopause. Thus, first linetreatment/prevention of this condition is inhibition of bone resorptionby bisphosphonates, estrogens, selective estrogen receptor modulators(SERMs) and calcitonin. However, inhibitors of bone resorption are notsufficient to restore bone mass for patients who have already lost asignificant amount of bone. The increase in spinal BMD attained bybisphosphonate treatment can reach 11% after 7 years of treatment withalendronate. In addition, as the rate of bone turnover differs from siteto site; higher in the trabecular bone of the vertebrae than in thecortex of the long bones, the bone resorption inhibitors are lesseffective in increasing hip BMD and preventing hip fracture. Therefore,osteoanabolic agents, which increase cortical/periosteal bone formationand bone mass of long bones, would address an unmet need in thetreatment of osteoporosis especially for patients with high risk of hipfractures.

A number of studies demonstrate that androgens are osteoanabolic inwomen and men. Anabolic steroids, such as nandrolone decanoate orstanozolol, have been shown to increase bone mass in postmenopausalwomen. Beneficial effects of androgens on bone in post-menopausalosteoporosis are well documented in recent studies using combinedtestosterone and estrogen administration (Hofbauer, et al., Androgeneffects on bone metabolism: recent progress and controversies, Eur. J.Endocrinol. 140, 271-286, 1999). Thus those compounds of Formula Iexhibiting agonist or partial agonist activity may be used to treat, oralleviate, osteoporosis, including primary osteoporosis such as senile,postmenopausal and juvenile osteoporosis, as well as secondaryosteoporosis, such as osteoporosis due to hyperthyroidism or Cushingsyndrome (due to corticosteroid treatment), acromegaly, hypogonadism,dysosteogenesis and hypophosphatasemia. Other bone related indicationsamendable to treat from androgen agonists include osteoporotic fracture,childhood idiopathic bone loss, alveolar bone loss, mandibular boneloss, bone fracture, osteotomy, periodontitis, or prosthetic ingrowth.

Those compounds acting as agonists, or partial agonists, can also beused to stimulate muscle mass in patients afflicted with wastingdiseases, such as AIDS, cancer cachexia, burns, renal disease, etc.Patients suffering from trauma, bedsores, age, etc. can also benefitsfrom the anabolic effects of androgens.

Co-Administration

In a further embodiment of the invention, the compounds of Formula I canbe co-administered with other compounds to further enhance theiractivity, or to minimize potential side effects. For example, potassiumchannel openers, such as minoxidil, are known to stimulate hair growthand to induce anagen. Examples of other potassium channel openersinclude(3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran,diaxozide, and PO 1075 which is under development by LeoPharmaceuticals. Such compounds can be co-administered with thecompounds of Formula I to alleviate alopecia

Thyroid hormone is also known to stimulate hair growth. Syntheticthyroid hormone replacements (i.e. thyromimetics) have also been shownto stimulate hair growth. Such thyromimetics have been described in theliterature previously. The reader's attention is directed to EuropeanPatent Application No. 1262177, the contents of which are herebyincorporated by reference, for a discussion of such compounds and theiruse to alleviate alopecia. One particular compound of interest is2-{4-[3-(4-Fluoro-benzyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2H-[1,2,4]triazine-3,5-dione.Such compounds can be co-administered with the compounds of Formula I toalleviate alopecia.

Anti-androgens can work by a number of different mechanisms. Forexample, some compounds block the conversion of testosterone to5-α-dihydrotestosterone, which is responsible for the biological effectin many tissues. 5-Alpha-reductase inhibitors, such as finasteride, havebeen shown to stimulate hair growth. Finasteride is commerciallyavailable from Merck under the trade name Propecia®. Examples of other5-α-reductase inhibitors include dutasteride (Glaxo Smithkline). Suchcompounds can be co-administered with the compounds of Formula I toalleviate alopecia.

Protein kinase C inhibitors have also been shown to stimulate hairgrowth and induce anagen. Calphostin C, which is a selective inhibitorof protein kinase C, has been shown to induce anagen. Other selectiveprotein kinase C inhibitors, such as hexadecylphosphocholine,palmitoyl-DL-carnitine chloride, and polymyxin B sulfate have also beenshown to induce anagen. Skin Pharmacol Appl Skin Physiol 2000May-August; 13(3-4):133-42 Any such protein kinase C inhibitor can beco-administered with a compound of Formula I to alleviate alopecia.

Immunophilins are a family of cytoplasmic proteins. Their ligandsinclude cyclosporin, FK506, and rapamycin. They are derived from fungiand were developed primarily for their potent immunosuppressiveproperties. Cyclosporin binds to the protein, cyclophilin, while FK506and rapamycin bind to FK binding protein (FKBP). All of these compoundshave been shown to stimulate hair growth and induce anagen. Any suchimmunophilin ligands can be co-administered with a compound of Formula Ito alleviate alopecia.

As used in this application, co-administered refers to administering acompound of Formula I with a second anti-alopecia agent, typicallyhaving a differing mechanism of action, using a dosing regimen thatpromotes hair growth in the patient. This can refer to simultaneousdosing, dosing at different times during a single day, or even dosing ondifferent days. The compounds can be administered separately or can becombined into a single formulation. Techniques for preparing suchformulations are described below.

Formulations

If desired, the compounds can be administered directly without anycarrier. However, to ease administration, they will typically beformulated into pharmaceutical carriers. Likewise, they will mosttypically be formulated into dermatological, or cosmetic carriers. Inthis application the terms “dermatological carrier” and “cosmetic”carrier are being used interchangeably. They refer to formulationsdesigned for administration directly to the skin or hair.

Pharmaceutical and cosmetic compositions can be manufactured utilizingtechniques known in the art. Typically an effective amount of thecompound will be admixed with a pharmaceutically/cosmetically acceptablecarrier.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, lozenges, melts,powders, suspensions, or emulsions. Solid unit dosage forms can becapsules of the ordinary gelatin type containing, for example,surfactants, lubricants and inert fillers such as lactose, sucrose, andcornstarch or they can be sustained release preparations.

In another embodiment, the compounds of Formula I can be tableted withconventional tablet bases such as lactose, sucrose, and cornstarch incombination with binders, such as acacia, cornstarch, or gelatin,disintegrating agents such as potato starch or alginic acid, and alubricant such as stearic acid or magnesium stearate. Liquidpreparations are prepared by dissolving the active ingredient in anaqueous or non-aqueous pharmaceutically acceptable solvent, which mayalso contain suspending agents, sweetening agents, flavoring agents, andpreservative agents as are known in the art.

For parenteral administration the compounds may be dissolved in aphysiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Illustrative of suitablepharmaceutical carriers are water, saline, dextrose solutions, fructosesolutions, ethanol, or oils of animal, vegetative, or synthetic origin.The pharmaceutical carrier may also contain preservatives, buffers,etc., as are known in the art. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid as isknown in the art.

The compounds of this invention will typically be administeredtopically. As used herein, topical refers to application of thecompounds (and optional carrier) directly to the skin and/or hair. Thetopical composition according to the present invention can be in theform of solutions, lotions, salves, creams, ointments, liposomes,sprays, gels, foams, roller sticks, or any other formulation routinelyused in dermatology.

Thus, a further embodiment relates to cosmetic or pharmaceuticalcompositions, in particular dermatological compositions, which compriseat least one of the compounds corresponding to Formula I above. Suchdermatological compositions will contain from 0.001% to 10% w/w % of thecompounds in admixture with a dermatologically acceptable carrier, andmore typically, from 0.1 to 5 w/w % of the compounds. Such compositionswill typically be applied from 1 to 4 times daily. The reader'sattention is directed to Remington's Pharmaceutical Science, Edition 17,Mack Publishing Co., Easton, Pa. for a discussion of how to prepare suchformulations.

The compositions according to the invention can also consist of solidpreparations constituting cleansing soaps or bars. These compositionsare prepared according to the usual methods.

The compounds can also be used for the hair in the form of aqueous,alcoholic or aqueous-alcoholic solutions, or in the form of creams,gels, emulsions or mousses, or alternatively in the form of aerosolcompositions also comprising a propellant under pressure. Thecomposition according to the invention can also be a hair carecomposition, and in particular a shampoo, a hair-setting lotion, atreating lotion, a styling cream or gel, a dye composition, a lotion orgel for preventing hair loss, etc. The amounts of the variousconstituents in the dermatological compositions according to theinvention are those conventionally used in the fields considered.

The medicinal and cosmetics containing the compounds of the inventionwill typically be packaged for retail distribution (i.e. an article ofmanufacture). Such articles will be labeled and packaged in a manner toinstruct the patient how to use the product. Such instructions willinclude the condition to be treated, duration of treatment, dosingschedule, etc.

The compounds of Formula I may also be admixed with any inert carrierand utilized in laboratory assays in order to determine theconcentration of the compounds within the serum, urine, etc., of thepatient as is known in the art. The compounds may also be used as aresearch tool.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention. The following examples and biological datais being presented in order to further illustrate the invention. Thisdisclosure should not be construed as limiting the invention in anymanner.

EXAMPLES Example 12-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic AcidBenzylamide

Step 1:

2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid isopropylester (1A) is prepared by the following method:

The starting materials, DL-leucic acid isopropyl ester (5.22 g in 100 mlof dry THF, 30 mmol) and NaH (1.4 g, 36 mmol) are stirred at 0° C. underN₂ for 15 min., then 4-fluoro-2-trifluoromethyl-benzonitrile (5.67 g, 30mmol), is added, the reaction mixture is stirred at 0° C. for 1 hour,then room temperature for 3 hours. It is quenched with saturated NaHCO₃,extracted with ethyl acetate. The crude product is purified by column toyield an oily liquid as the pure product. (7 g).

Step 2: 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(1B)

An admixture of 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid isopropyl ester (1A) (0.22 g, 0.67 mmol in 20 ml of drytetrahydrofuran “THF”), LiOH (0.28 g, 6.7 mmol) and water (20 ml) isrefluxed at 100° C. for 3 hours, then it is cooled to room temperature,the THF is removed, the crude product is diluted with 100 ml of ethylacetate, and HCl (1N) to adjusted PH=1. The organic layer is separatedand dried on vacuum to get the desired product.

Step 3: 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic AcidBenzylamide (Example 1)

An admixture of 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid (1B) (0.20 g, 0.67 mmol in 20 ml of dimethylformamide “DMF”benzylamine (0.16 g, 1.59 mmol), diisopropyl ethylamine (0.26 g, 2 mmol)and 1-H-Benzotriazolium (“HBTU”) (0.25 g, 0.67 mmol) is stirred at roomtemperature (“RT”) for 4 hours, then the reaction is diluted with ethylacetate, it is then washed with saturated NaHCO₃ (three times), theorganic layer is separated and the solvent is removed to yield the crudeproduct, it is purified by liquid chromatography mass spectroscopy(“LCMS”) using the eluent described below.

MS: 391.1 (M+1 for C₂₁H₂₁N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 1.46 min Purity: 100%.

Example 2 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic AcidIsopropylamide

The product of Example 2 is prepared analogously to Example 1, exceptisopropyl amine is used instead of benzyl amine in Step 3. The desiredproduct is purified by silica gel column:

MS: 343.2 (M+1 for C₁₇H₂₁N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 1.21 min Purity: 100%.

Example 3 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic AcidEthylamide

The product of Example 3 is prepared analogously to Example 1, exceptethylamine is used instead of benzyl amine in Step 3. The desiredproduct is purified by silica gel column.

MS: 329.2 (M+1 for C₁₆H₁₉N₂F₃O₂) LCMS: C-18 Column (50% H₂O/50% CH₃CN),Ret. Time: 2.65 min Purity: 100%.

Example 4 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic AcidBenzylamide

The product of Example 4 is prepared analogously to example 1, except instep 1, DL-2-hydroxy-pentanoic acid ethyl ester is used instead ofDL-leucic acid isopropyl ester as one of the starting materials. Thedesired product is purified by silica gel column.

MS: 377.1 (M+1 for C₂₀H₁₉N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 1.31 min Purity: 100%.

Example 5 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic AcidEthylamide

The product of Example 5 is prepared analogously to example 1, exceptethylamine is used instead of benzyl amine in Step 3. The desiredproduct is purified by silica gel column.

MS: 315.1 (M+1 for C₁₅H₁₇N₂F₃O₂) LCMS: C-18 Column (50% H₂O/50% CH₃CN),Ret. Time: 2.31 min Purity: 100%.

Example 6 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid[1-(4-hydroxy-phenyl)-ethyl]-amide

The product of Example 6 is prepared analogously to Example 1, exceptthat 4-(1-amino-ethyl)-phenol is used instead of benzyl amine in Step 3.The desired product is purified by silica gel column.

MS: 407.35 (M+1 for C₂₁H₂₁F₃N₂O₃. LCMS: Polar RP-Phenyl column 100mm×4.6 mm, 4 mm (Solvent: A=Water w/0.1M Formic Acid; B=Acetonitrilew/0.1M Formic Acid, Method: 0-2.5 min: 95% A, 10% B; 2.5-5.1 min: 2% A,98% B; 5.1-7 min: 95% A, 5% B), Ret. Time: 3.81 min. Purity: 100%.

Example 7 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acidcyclopropylmethyl-amide

The product of Example 7 is prepared analogously to Example 1, exceptcyclopropylmethyl amine is used instead of benzyl amine in Step 3. Thedesired product is purified by silica gel column.

MS: 355.1 (M+1 for C₁₈H₂₁N₂F₃O₂) LCMS: C-18 Column (50% H₂O/50% CH₃CN),Ret. Time: 3.09 min Purity: 100%.

Example 8 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acidisobutyl-amide

The product of Example 8 is prepared analogously to example 1, exceptisobutyl amine is used instead of benzyl amine in Step 3. The desiredproduct is purified by silica gel column.

MS: 357.1 (M+1 for C₁₈H₂₃N₂F₃O₂) LCMS: C-18 Column (50% H₂O/50% CH₃CN),Ret. Time: 2.53 min Purity: 100%.

Example 9 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid[2-(4-methoxy-phenyl)-ethyl]-amide

The product of Example 9 is prepared analogously to example 1, except2-(4-methoxy-phenyl)-ethyl amine is used instead of the benzyl amine inStep 3. The desired product is purified by silica gel column.

MS: 435.33 (M+1 for C₂₃H₂₅N₂F₃O₃) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 4.54 min Purity: 89%.

Example 10 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2-phenoxy-ethyl)-amide

The product of Example 10 is prepared analogously to example 1, except2-phenoxy-ethyl amine is used instead of the benzyl amine in Step 3. Thedesired product is purified by LCMS as described below.

MS: 421.22 (M+1 for C₂₃H₂₃F₃N₂O₃). LCMS: Phen Aqua C18 4.6 um×100 um, 3mm column (Solvent: A=Water w/0.1M Formic Acid; B=Acetonitrile w/0.1MFormic Acid, Method: 0-3 min: 90% A, 10% B; 3-5.1 min: 2% A, 98% B;5.1-7 min: 90% A, 10% B), Ret. Time: 4.47 min. Purity: 100%.

Examples 11-90

The products of Examples 11-90, 115, and 116 were prepared bycombinatorial chemistry, as described below, using the synthesisdescribed in Reaction Scheme II above (i.e. amidation). One of thereactants was a compound of Formula I in which Y is OH, either2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid or2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic. These compounds wereprepared as described in Examples 1 and 4, above. The other reactant wasthe appropriate amine, as described by structure 4 above in which X² andX³ correspond to the final product.

The compounds depicted below in Examples 11, 12, 13, 15, 16, 17, 19, 20,21, 22 were prepared in the following manner. To 1 mL of 0.1M (molar)solutions of either2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid or2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid indimethylformamide “DMF” (0.1 mmol) was added 1.0 mL of a 0.12M solutionof 1-hydroxybenzotriazole “HOBT” (0.12 mmol) in DMF, 0.3 mL of a 1.0Msolution of the appropriate amine of structure 4 (0.3 mmol) in DMF, andapproximately 64 mg of polystyrene bound carbodiimide (loading: 1.9mmol/g, 0.12 mmol). The resultant mixture was shaken and heated at 70°C. for approximately 18 hours. The reaction was cooled to RT andapproximately 40 mg of macroporous polystyrene bound carbonate (loading:3.21 mmol/g, 0.128 mmol) was added. The resultant mixture was shaken atroom temperature for approximately 18 hours. To the reaction was added1.0 mL of a 0.12M solution of HOBT (0.12 mmol) in DMF, 0.3 mL of a 1.0Msolution of the appropriate amine of structure 4 (0.3 mmol) in DMF, andapproximately 64 mg of polystyrene bound carbodiimide (loading: 1.9mmol/g, 0.12 mmol). The resultant mixture was shaken and heated at 70°C. for approximately 18 hours. The reaction was cooled to roomtemperature and approximately 288 mg of polystyrene bound isocyanate(loading: 2.08 mmol/g, 0.6 mmol) and approximately 40 mg of macroporouspolystyrene bound carbonate was added. The resultant mixture was shakenat room temperature for approximately 30 min., filtered and the resinwas thoroughly rinsed with tetrahydrofuran. The solvent was removed invacuo using an evaporator, Genevac HT-12, to obtain a sample that waspurified by HPLC (“high performance liquid chromatography”.

The compounds depicted below in Examples 9, 10, 14,18,23-27, 29-68 wereprepared in the following manner. To 1 mL of 0.1M solutions of either2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid or2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid in DMF (0.1 mmol)was added 1.0 mL of a 0.24M solution of HOBT (0.24 mmol) in DMF, 0.6 mLof a 1.0M solution of the appropriate amine of structure 4 (0.6 mmol) inDMF, and approximately 126 mg of polystyrene bound carbodiimide(loading: 1.9 mmol/g, 0.24 mmol). The resultant mixture was shaken andheated at 70° C. for approximately 22 hours. The reaction was cooled toRT and approximately 100 mg of macroporous polystyrene bound carbonate(loading: 2.64 mmol/g, 0.264 mmol) and approximately 150 mg ofmacroporous polystyrene bound tosic acid resin (loading: 4.07 mmol/g,0.610 mol) was added. The resultant mixture was shaken at roomtemperature for approximately 18 hours. To the reaction was added 1.0 mLof a 0.24M solution of HOBT (0.24 mmol) in DMF, 0.6 mL of a 1.0Msolution of the appropriate amine of structure 4 (0.6 mmol) in DMF, andapproximately 100 mg of polystyrene bound carbodiimide (loading: 1.9mmol/g, 0.19 mmol). The resultant mixture was shaken and heated at 70°C. for approximately 10 hours. The reaction was cooled to roomtemperature, filtered and the resin was thoroughly rinsed with methanol.The solvent was removed in vacuo using a high thru put evaporator,Genevac HT-12, to obtain a sample that was then purified by HPLC.

The compounds depicted below in Examples 6, 69-77 were prepared in thefollowing manner. To 1 mL of 0.1M solutions of either2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid or2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid in DMF (0.1 mmol)was added 1.0 mL of a 0.48M solution of HOBT (0.48 mmol) in DMF, andapproximately 226 mg of polystyrene bound carbodiimide (loading: 1.9mmol/g, 0.43 mmol). The resultant mixture was shaken at room temperaturefor 1 hour. To the reaction was added 0.6 mL of a 1.0M solution of theappropriate amine of structure 4 (0.6 mmol) in DMF. The resultantmixture was shaken and heated at 70° C. for approximately 22 hours. Thereaction was cooled to RT. Added 200 mg of polystyrene bound carbodimide(loading: 1.9 mmol/g, mmol) and 65 mg of HOBT to the reaction. Theresultant mixture was shaken at 70° C. for approximately 15 hours. Thereaction was cooled to RT and approximately 379 mg of macroporouspolystyrene bound carbonate (loading: 2.64 mmol/g, 1 mmol) was added toeach vial. The resultant mixture was shaken at room temperature forapproximately 18 hours. Filtered and the resin was thoroughly rinsedwith methanol. The solvent was removed in vacuo using a Genevac HT-12 toobtain a sample that was then purified by HPLC.

The compounds depicted below in Examples 78-90 were prepared in thefollowing manner. To 0.5 mL of 0.2M solutions of either2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid or2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid in DMF (0.1 mmol)was added 1.0 mL of a 0.4M solution of HOBT (0.2 mmol) in DMF, andapproximately 183 mg of polystyrene bound carbodiimide (loading: 1.9mmol/g, 0.2 mmol), and 0.1 mL of a 1.0M solution of the appropriateamine of structure 4 (0.1 mmol) in DMF. The resultant mixture was shakenand heated at 70° C. for approximately 22 hours. The reaction was cooledto RT. Filtered and the resin was thoroughly rinsed with methanol. Thesolvent was removed in vacuo using a Genevac HT-12 to obtain a samplethat was then purified by HPLC.

The compounds depicted below in Examples 115 and 116 were prepared inthe following manner. To 0.5 mL of 0.2M solutions of either2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid or2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid indimethylformamide “DMF” (0.1 mmol) were added 1.0 mL of a 0.4M solutionof 1-hydroxybenzotriazole “HOBT” (0.2 mmol) in DMF, and approximately183 mg of polystyrene bound carbodiimide (loading: 1.9 mmol/g, 0.2mmol), and 0.1 mL of a 1.0M solution of the appropriate amine ofstructure 4 (0.1 mmol) in DMF. The resultant mixtures were shaken andheated at 70° C. for approximately 22 hours. The reactions were cooledto RT. Filtered and the resin was thoroughly rinsed with methanol. Thesolvent was removed in vacuo using a Genevac HT-12 to obtain samplesthat were then purified by HPLC.

Three different HPLC (high performance liquid chromatography) methodswere utilized to purify the compounds. These methods are summarizedbelow:

1) Method A

HPLC Conditions:

Column: BHK 30×100 mm ODS-A 5 μm C-18.

Flow rate: 30 mL/min

Solvent: A=Acetonitrile w/3% 1-Propanol; B=Water w/3% 1-Propanol

Method: 0-6.5 min: 15% A, 85% B; 6.5-10.5 min: 100% A

2) Method B

HPLC Conditions:

Column: YMC 30×100 mm ODS-A 5 μm C-18.

Flow rate: 30 mL/min

Solvent: A=Acetonitrile w/3% 1-Propanol; B=Water w/3% 1-Propanol

Method: 0-6.5 min: 15% A, 85% B; 6.5-10.5 min: 100% A

3) Method C

HPLC Conditions:

Column: Xterra 30×100 mm 5 μm C-18.

Flow rate: 30 mL/min

Solvent: A=Acetonitrile w/3% 1-Propanol; B=Water w/3% 1-Propanol

Method: 0-6.5 min: 25% A, 75% B; 6.5-10.5 min: 100% A

The compounds were also subjected to liquid chromatographic massspectrometry (LCMS) using one of three methods as described below:

Method A

LCMS: Atlantis C18 5 cm×4.6 mm, 3 mm column (Solvent: A=Water w/0.1MFormic Acid; B=Acetonitrile w/0.1M Formic Acid, Method: 0-3 min: 90% A,10% B; 3-5.1 min: 2% A, 98% B; 5.1-7 min: 90% A, 10% B

Method B

LCMS: Phen Aqua C18 4.6 um×100 um, 3 mm column (Solvent: A=Water w/0.1MFormic Acid; B=Acetonitrile w/0.1M Formic Acid, Method: 0-3 min: 90% A,10% B; 3-5.1 min: 2% A, 98% B; 5.1-7 min: 90% A, 10% B),

Method C

LCMS: Polar RP-Phenyl column 100 mm×4.6 mm, 4 mm (Solvent: A=Waterw/0.1M Formic Acid; B=Acetonitrile w/0.1M Formic Acid, Method: 0-2.5min: 95% A, 10% B; 2.5-5.1 min: 2% A, 98% B; 5.1-7 min: 95% A, 5% B),

Example 11 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(furan-2-yl-methyl)-amide

HPLC—Method A

LCMS—Method A

MS: 381.2 (M+1 for C₁₉H₁₉F₃N₂O₃). Ret. Time: 3.64 min. Purity: 85.56%.

Example 12 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(thiophen-2-yl-methyl)-amide

HPLC—Method A

LCMS—Method A

MS: 397.24 (M+1 for C₁₉H₁₉F₃N₂O₂S). Ret. Time: 3.77 min. Purity: 94.55%.

Example 13 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(1-thiophen-2-yl-ethyl)-amide

HPLC—Method A

LCMS—Method A

MS: 411.23 (M+1 for C₂₀H₂₁F₃N₂O₂S). Ret. Time: 3.82 min. Purity: 98.38%.

Example 14 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(1-methyl-2-thiophen-3-yl-ethyl)-amide

HPLC—Method B

LCMS—Method B

MS: 425.22 (M+1 for C₂₁H₂₃F₃N₂O₂S). Ret. Time: 4.64 min. Purity: 100%.

Example 15 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(1-pyridin-3-yl-ethyl)-amide

HPLC—Method B

LCMS—Method A

MS: 406.29 (M+1 for C₂₁H₂₂F₃N₃O₂). Ret. Time: 3.19 min. Purity: 97.78%.

Example 16 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(pyridin-4-yl-methyl)-amide

HPLC—Method A

LCMS—Method A

MS: 392.29 (M+1 for C₂₀H₂₀F₃N₃O₂). Ret. Time: 2.87 min. Purity: 86.11%.

Example 17 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(1-thiophen-2-yl-ethyl)-amide

HPLC Method A

LCMS—Method B

MS: 397.19 (M+1 for C₁₉H₁₉F₃N₂O₂S). Ret. Time: 3.71 min. Purity: 100%.

Example 18 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(1-methyl-2-thiophen-3-yl-ethyl)-amide

HPLC Method B

LCMS—Method B

MS: 411.19 (M+1 for C₂₀H₂₁F₃N₂O₂S). Ret. Time: 4.52 min. Purity: 100%

Example 19 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(pyridin-3-yl-methyl)-amide

HPLC Method A

LCMS—Method A

MS: 392.25 (M+1 for C₂₀H₂₀F₃N₃O₂). Ret. Time: 3.06 min. Purity: 97.63%.

Example 20 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-methyl-pyridin-2-yl-methyl)-amide

HPLC Method A

LCMS—Method A

MS: 406.29 (M+1 for C₂₁H₂₂F₃N₃O₂). Ret. Time: 3.54 min. Purity: 87.09%.

Example 21 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-methylsulfanyl-propyl)-amide

HPLC Method C:

LCMS—Method A

MS: 389.21 (M+1 for C₁₈H₂₃F₃N₂O₂S). Ret. Time: 3.85 min. Purity: 95.92%.

Example 22 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-methyl-butyl)-amide

HPLC—Method A

LCMS—Method A

MS: 371.31 (M+1 for C₁₉H₂₅F₃N₂O₂). Ret. Time: 3.91 min. Purity: 98.91%.

Example 23 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3,3-diethoxy-propyl)-amide

HPLC—Method B

LCMS—Method B

MS: 385.31 (M+1 for C₂₁H₂₉F₃N₂O₄). Ret. Time: 4.61 min. Purity: 100%.

Example 24 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(benzo[1,3]dioxol-5-yl-methyl)-amide

HPLC—Method B

LCMS—Method B

MS: 435.28 (M+1 for C₂₂H₂₁F₃N₂O₄). Ret. Time: 4.46 min. Purity: 100%.

Example 25 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2,3-dihydro-benzofuran-5-yl-methyl)-amide

HPLC—Method B

LCMS—Method B

MS: 433.25 (M+1 for C₂₃H₂₃F₃N₂O₃). Ret. Time: 4.51 min. Purity: 100%.

Example 26 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(benzo[1,2,5]thiadiazol-5-yl-methyl)-amide

HPLC—Method B

LCMS—Method B

MS: 449.15 (M+1 for C₂₁H₁₉F₃N₄O₂S). Ret. Time: 4.54 min. Purity: 100%.

Example 27 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(isochroman-3-yl-methyl)-amide

HPLC—Method B

LCMS—Method B

MS: 447.25 (M+1 for C₂₄H₂₅F₃N₂O₃). Ret. Time: 4.66 min. Purity: 100%.

Example 28 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-methylsulfanyl-propyl)-amide

HPLC Method C

LCMS—Method A

MS: 389.21 (M+1 for C₁₈H₂₃F₃N₂O₂S). Ret. Time: 3.85 min. Purity: 95.92%.

Example 29 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(benzo[1,3]dioxol-5-yl-methyl)-amide

HPLC—Method B

LCMS—Method B

MS: 421.18 (M+1 for C₂₁H₁₉F₃N₂O₄). Ret. Time: 4.34 min. Purity: 100%.

Example 30 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(2,3-dihydro-benzofuran-5-yl-methyl)-amide

HPLC—Method

LCMS—Method B

MS: 419.19 (M+1 for C₂₂H₂₁F₃N₂O₃). Ret. Time: 4.37 min. Purity: 100%.

Example 31 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(benzo[1,2,5]thiadiazo-5-yl-methyl)-amide

HPLC—Method B

LCMS—Method B

MS: 435.18 (M+1 for C₂₀H₁₇F₃N₄O₂S). Ret. Time: 4.42 min. Purity: 100%.

Example 32 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(isochroman-3-yl-methyl)-amide

HPLC Method B

LCMS—Method B

MS: 433.24 (M+1 for C₂₃H₂₃F₃N₂O₃). Ret. Time: 4.56 min. Purity: 100%.

Example 33 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-3-methoxy-benzylamide

HPLC Method B

LCMS—Method B

MS: 421.3 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.51 min. Purity: 100%

Example 34 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid[2-(4-methoxy-phenyl)-ethyl]amide

HPLC Method B

LCMS—Method B

MS: 435.33 (M+1 for C₂₃H₂₅F₃N₂O₃). Ret. Time: 4.54 min. Purity: 89.19%.

Example 35 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-2-methoxy-benzylamide

HPLC—Method B

LCMS—Method B

MS: 421.28 (M+1 for C₂₂H₂₃F₃N₂O₃) Ret. Time: 4.59 min. Purity: 100%.

Example 36 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-2-ethoxy-benzylamide

HPLC—Method B

LCMS—Method B

MS: 435.33 (M+1 for C₂₃H₂₅F₃N₂O₃) Ret. Time: 4.69 min. Purity: 100%

Example 37 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-3-methyl-benzylamide

HPLC—Method B

LCMS—Method B

MS: 405.3 (M+1 for C₂₂H₂₃F₃N₂O₂). Ret. Time: 4.64 min. Purity: 100%.

Example 38 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-2-methyl-benzylamide

HPLC—Method B

LCMS—Method B

MS: 405.3 (M+1 for C₂₂H₂₃F₃N₂O₂). Ret. Time: 4.64 min. Purity: 100%.

Example 39 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-4-methoxy-benzylamide

HPLC—Method B

LCMS—Method B

MS: 421.31 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.46 min. Purity: 100%.

Example 40 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-3-methoxy-benzylamide

HPLC—Method B

LCMS—Method B

MS: 407.22 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 4.41 min. Purity: 100%.

Example 41 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-2-methoxy-benzylamide

HPLC—Method B

LCMS—Method B

MS: 407.22 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 4.49 min. Purity: 100%.

Example 42 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-2-ethoxy-benzylamide

HPLC—Method B

LCMS—Method B

MS: 421.22 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.64 min. Purity: 100%.

Example 43 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-3-methyl-benzylamide

HPLC—Method B

LCMS—Method B

MS: 391.22 (M+1 for C₂₁H₂₁F₃N₂O₂). Ret. Time: 4.54 min. Purity: 100%.

Example 44 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-2-methyl-benzylamide

HPLC—Method B

LCMS—Method B

MS: 391.22 (M+1 for C₂₁H₂₁F₃N₂O₂). Ret. Time: 4.54 min. Purity: 100%.

Example 45 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-2,4-dimethyl-benzylamide

HPLC—Method B

LCMS—Method B

MS: 405.22 (M+1 for C₂₂H₂₃F₃N₂O₂). Ret. Time: 4.62 min. Purity: 100%.

Example 46 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-4-methoxy-benzylamide

HPLC—Method B

LCMS—Method B

MS: 407.22 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 4.39 min. Purity: 100%.

Example 47 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-(2-p-tolyl-ethyl)-amide

HPLC—Method B

LCMS—Method B

MS: 419.32 (M+1 for C₂₃H₂₅F₃N₂O₂). Ret. Time: 4.72 min. Purity: 100%.

Example 48 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-[2-(2-methoxy-phenyl)-ethyl]-amide

HPLC—Method B

LCMS—Method B

MS: 435.3 (M+1 for C₂₃H₂₅F₃N₂O₃). Ret. Time: 4.67 min. Purity: 100%.

Example 49 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-(2-m-tolyl-ethyl)-amide

HPLC—Method B

LCMS—Method B

MS: 419.25 (M+1 for C₂₃H₂₅F₃N₂O₂). Ret. Time: 4.71 min. Purity: 100%.

Example 50 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-(2-p-tolyl-ethyl)-amide

HPLC—Method B

LCMS—Method B

MS: 405.23 (M+1 for C₂₂H₂₃F₃N₂O₂). Ret. Time: 4.64 min. Purity: 100%.

Example 51 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-[2-(2-methoxy-phenyl)-ethyl]-amide

HPLC—Method B

LCMS—Method B

MS: 421.23 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.57 min. Purity: 100%.

Example 52 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-(2-m-tolyl-ethyl)-amide

HPLC—Method B

LCMS—Method B

MS: 405.22 (M+1 for C₂₂H₂₃F₃N₂O₂). Ret. Time: 4.62 min. Purity: 100%.

Example 53 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-(2-phenoxy-propyl)-amide

HPLC—Method B

LCMS—Method B

MS: 435.24 (M+1 for C₂₃H₂₅F₃N₂O₃). Ret. Time: 4.69 min. Purity: 100%.

Example 54 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acidindan-1-yl-amide

HPLC—Method B

LCMS—Method B

MS: 417.25 (M+1 for C₂₃H₂₃F₃N₂O₂). Ret. Time: 4.71 min. Purity: 100%.

Example 55 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-(2-phenoxy-propyl)-amide

HPLC—Method B

LCMS—Method B

MS: 421.2 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.59 min. Purity: 100%.

Example 56 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-(2-phenoxy-ethyl)-amide

HPLC—Method B

LCMS—Method B

MS: 407.21 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 4.47 min. Purity: 94.67%

Example 57 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acidindan-1-yl-amide

HPLC—Method B

LCMS—Method B

MS: 403.24 (M+1 for C₂₂H₂₁F₃N₂O₂). Ret. Time: 4.61 min. Purity: 100%.

Example 58 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-[2-(3-methoxy-phenyl)-ethyl]-amide

HPLC—Method B

LCMS—Method B

MS: 435.33 (M+1 for C₂₃H₂₅F₃N₂O₃). Ret. Time: 4.56 min. Purity: 79.59%.

Example 59 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid[2-(1H-indol-3-yl)-ethyl]amide

HPLC—Method B

LCMS—Method B

MS: 444.3 (M+1 for C₂₄H₂₄F₃N₃O₂). Ret. Time: 4.52 min. Purity: 100%.

Example 60 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2H-imidazo[1,2-a]pyridin-3-yl)-methyl)amide

HPLC—Method B

LCMS—Method B

MS: 445.24 (M+1 for C₂₃H₂₃F₃N₄O₂). Ret. Time: 2.96 min. Purity: 100%.

Example 61 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-[2-(4-hydroxy-phenyl)-ethyl]-amide

HPLC—Method B

LCMS—Method B

MS: 421.29 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.21 min. Purity: 100%

Example 62 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-(3-pyridin-3-yl-propyl)-amide

HPLC—Method B

LCMS—Method B

MS: 420.24 (M+1 for C₂₂H₂₄F₃N₃O₂). Ret. Time: 3.66 min. Purity: 94.76%.

Example 63 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acidbenzyl-isopropyl-amide

HPLC—Method B

LCMS—Method B

MS: 433.28 (M+1 for C₂₄H₂₇F₃N₂O₂). Ret. Time: 4.87 min. Purity: 100%.

Example 64 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-[2-(3-methoxy-phenyl)-ethyl]-amide

HPLC—Method B

LCMS—Method B

MS: 421.24 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.46 min. Purity: 82.38%.

Example 65 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid[2-(1H-indol-3-yl)-ethyl]amide

HPLC—Method B

LCMS—Method B

MS: 430.22 (M+1 for C₂₃H₂₂F₃N₃O₂). Ret. Time: 4.41 min. Purity: 100%.

Example 66 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-[2-(4-hydroxy-phenyl)-ethyl]-amide

HPLC—Method B

LCMS—Method B

MS: 407.21 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 4.07 min. Purity: 100%.

Example 67 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acidbenzyl-isopropyl-amide

HPLC—Method B

LCMS—Method B

MS: 419.24 (M+1 for C₂₃H₂₅F₃N₂O₂). Ret. Time: 4.74 min. Purity: 100%.

Example 68 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2-dimethylamino-2-phenyl-ethyl)-amide

HPLC—Method B

LCMS—Method B

MS: 448.29 (M+1 for C₂₄H₂₈F₃N₃O₂). Ret. Time: 3.01 min. Purity: 90.27%.

Example 69 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid[1-(4-hydroxy-phenyl)-ethyl]-amide

HPLC—Method A

LCMS—Method C

MS: 421.33 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 3.92 min. Purity: 100%.

Example 70 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid4-isopropyl-benzylamide

HPLC—Method A

LCMS—Method C

MS: 433.43 (M+1 for C₂₄H₂₇F₃N₂O₂). Ret. Time: 4.57 min. Purity: 100%.

Example 71 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-3-methoxy-benzylamide

HPLC—Method A

LCMS—Method C

MS: 421.4 (M+1 for C₂₂H₂₃F₃N₂O₃). Ret. Time: 4.51 min. Purity: 100%.

Example 72 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-(6-methoxy-pyridin-3-yl-methyl)-amide

HPLC—Method A

LCMS—Method C

MS: 422.39 (M+1 for C₂₁H₂₂F₃N₃O₃). Ret. Time: 4.07 min. Purity: 100%.

Example 73 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-4-methoxy-benzylamide

HPLC—Method A

LCMS—Method C

MS: 421.36 (M+1 for C₂₂H₂₃F₃N₂O₃), Ret. Time: 4.46 min. Purity: 100%.

Example 74 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-3,4-dihydroxy-benzylamide

HPLC—Method A

LCMS—Method C

MS: 423.32 (M+1 for C₂₁H₂₁F₃N₂O₄). Ret. Time: 3.67 min. Purity: 100%.

Example 75 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-(2-methyl-butyl)-amide

HPLC—Method A

LCMS—Method C

MS: 406.36 (M+1 for C₂₁H₂₂F₃N₃O₂). Ret. Time: 3.09 min. Purity: 86.9%.

Example 76 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2-methyl-pyridin-3-yl-methyl)-amide

HPLC—Method A

LCMS—Method C

MS: 406.36 (M+1 for C₂₁H₂₂F₃N₃O₂). Ret. Time: 3.09 min. Purity: 86.9%.

Example 77 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(naphthalene-1-yl-methyl)-amide

HPLC—Method A

LCMS—Method C

MS: 427.36 (M+1 for C₂₄H₂₁F₃N₂O₂). Ret. Time: 4.31 min. Purity: 94.82%.

Example 78 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-hydroxy-4-methyl-phenyl)-amide

HPLC—Method C

LCMS—Method A

MS: 407.23 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 3.78 min. Purity: 100%.

Example 79 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2-hydroxy-ethyl)-isopropyl-amide

HPLC—Method C

LCMS—Method A

MS: 387.24 (M+1 for C₁₉H₂₅F₃N₂O₃). Ret. Time: 3.71 min. Purity: 90.41%.

Example 80 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-methylsulfanyl-propyl)-amide

HPLC—Method C

LCMS—Method A

MS: 389.21 (M+1 for C₁₈H₂₃F₃N₂O₂S). Ret. Time: 3.67 min. Purity: 88.25%.

Example 81 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2-propoxy-ethyl)-amide

HPLC—Method C

LCMS—Method A

MS: 387.24 (M+1 for C₁₉H₂₅F₃N₂O₃). Ret. Time: 3.93 min. Purity: 100%.

Example 82 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(1-methoxymethyl-propyl)-amide

HPLC—Method C

LCMS—Method A

MS: 387.24 (M+1 for C₁₉H₂₅F₃N₂O₃). Ret. Time: 3.86 min. Purity: 93.3%.

Example 83 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2-methylsulfanyl-ethyl)-amide

HPLC—Method C

LCMS—Method A

MS: 375.21 (M+1 for C₁₇H₂₁F₃N₂O₂S). Ret. Time: 3.83 min. Purity: 89.41%.

Example 84 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-hydroxy-2-methyl-phenyl)-amide

HPLC—Method C

LCMS—Method A

MS: 407.19 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 3.69 min. Purity: 95.35%.

Example 85 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-propoxy-propyl)-amide

HPLC—Method C

LCMS—Method A

MS: 401.28 (M+1 for C₂₀H₂₇F₃N₂O₃). Ret. Time: 4 min. Purity: 100%.

Example 86 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acidethyl(2-methoxy-ethyl)-amide

HPLC—Method C

LCMS—Method A

MS: 387.24 (M+1 for C₁₉H₂₅F₃N₂O₃). Ret. Time: 3.97 min. Purity: 92.25%.

Example 87 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(2-methoxy-phenyl)-amide

HPLC—Method C

LCMS—Method A

MS: 407.2 (M+1 for C₂₁H₂₁F₃N₂O₃). Ret. Time: 4.15 min. Purity: 100%.

Example 88 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid(3-hydroxy-4-methyl-phenyl)-amide

HPLC—Method C

LCMS—Method C

MS: 393.21 (M+1 for C₂₀H₁₉F₃N₂O₃). Ret. Time: 3.69 min. Purity: 100%.

Example 89 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(3-methylsulfanyl-propyl)-amide

HPLC—Method C

LCMS—Method A

MS: 375.2 (M+1 for C₁₇H₂₁F₃N₂O₂S). Ret. Time: 3.75 min. Purity: 96.91%.

Example 90 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(2-methylsulfanyl-ethyl)-amide

HPLC—Method C

LCMS—Method A

MS: 361.21 (M+1 for C₁₆H₁₉F₃N₂O₂S). Ret. Time: 3.72 min. Purity: 94.75%.

Example 91 2-(4-Cyano-3-trifluoromethyl-phenoxy)-hexanoic AcidBenzylamide

The product of Example 91 is prepared analogously to example 1, exceptin step 1, ethyl-DL-2-hydroxy-cuproate is used instead of DL-leucic acidisopropyl ester as one of the starting materials. The desired product ispurified by silica gel column.

MS: 391 (M+1 for C₂₁H₂₁N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 1.51 min Purity: 100%.

Example 92N-Benzyl-2-(4-Cyano-3-trifluoromethyl-phenoxy)-3-methyl-butyramide

The product of Example 92 is prepared analogously to example 1, exceptin step 1, DL-2-hydroxy-3-methylbutyric acid is used instead ofDL-leucic acid isopropyl ester as one of the starting materials. Thedesired product is purified by silica gel column.

MS: 377 (M+1 for C₂₀H₁₉N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 2.9 min Purity: 100%.

Example 93 N-Benzyl-2-(4-Cyano-3-trifluoromethyl-phenoxy)-butyramide

The product of Example 93 is prepared analogously to example 1, exceptin step 1, DL-2-hydroxy-n-butyric acid ethyl ester is used instead ofDL-leucic acid isopropyl ester as one of the starting materials. Thedesired product is purified by silica gel column.

MS: 363 (M+1 for C₁₉H₁₇N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 1.07 min Purity: 100%.

Example 94 (R)-2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid Benzylamide

The product of Example 94 was prepared by chiral HPLC separation of theproduct of Example 1. The desired product was purified by LCMS asdescribed below.

MS: 391.1 (M+1 for C₂₁H₂₁N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 1.46 min Purity: 100%. [α]_(589(MeOH))=+37°.

Example 95 (R)-2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic AcidBenzylamide

The product of Example 95 was prepared by chiral HPLC separation of theproduct of Example 4.

MS: 377.1 (M+1 for C₂₀H₁₉N₂F₃O₂) LCMS: C-18 Column (25% H₂O/75% CH₃CN),Ret. Time: 1.31 min Purity: 100%. [α]_(589(MeOH))=+32°.

Example 96 (R)-2-(Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid2-methyl-benzylamide

The product of Example 96 was prepared by chiral HPLC separation of theproduct of Example 44.

Column: ChiralPak AD.

Hexane 80%/IPA 20%

Flow rate: 0.5 mL/min.

Retention time: 10.63 min.

[α]589 (MeOH)=+21.73°

Example 97 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide

The compound was prepared in the following manner. To 0.25 gm (0.87mmol) of 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid indimethylformamide “DMF” (15 mL) were added 0.14 gm (1.09 mmol) of1-Hydroxy-benzotriazole HOBT, 0.2 gm (1.09 mmol) of(3-(dimethylamino)propyl)ethylcarbodiimide EDCl, 0.23 gm (2.39 mmol)N-methyl morpholine, and approximately 246 mg of 5-methoxytryptaminehydrochloride (1.09 mmol). The resultant mixtures were stirred at roomtemperature for approximately 18 hours. The reactions were quenched withsodium bicarbonate (20 mL) and extracted with ethyl acetate (3 times 20mL). The solvent was removed in vacuo to obtain oils that were thenpurified by HPLC.

Prep HPLC Conditions

A: Water w/0.1% NH₄OH

B: Acetonitrile w/0.1% NH₄OH

5% to 95% B over 15 min.

1 min. ramp to 5% B, hold for 5 min.

Xterra C₁₈ 5 νμ, 4.6×150 mm

Retention time: 12.3 min.

Example 98 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic Acid[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide

The compound was prepared in the following manner. To 0.25 gm (0.83mmol) of 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acidin dimethylformamide “DMF” (15 mL) were added 0.14 gm (1.04 mmol) of1-Hydroxy-benzotriazole HOBT, 0.2 gm (1.04 mmol) of(3-(dimethylamino)propyl)ethylcarbodiimide EDCl, 0.23 gm (2.28 mmol)N-methyl morpholine, and approximately 234 mg of 5-methoxytryptaminehydrochloride (1.04 mmol). The resultant mixtures were stirred at roomtemperature for approximately 18 hours. The reactions were quenched withsodium bicarbonate (20 mL) and extracted with ethyl acetate (3 times 20mL). The solvent was removed in vacuo to obtain oils that were thenpurified by HPLC.

Prep HPLC Conditions

A: Water w/0.1% NH₄OH

B: Acetonitrile w/0.1% NH₄OH

5% to 95% B over 15 min.

1 min. ramp to 5% B, hold for 5 min.

Xterra C₁₈ 5 νμ, 4.6×150 mm

Retention time: 12.8 min.

Example 99 2-(3-Chloro-4-cyano-phenoxy)-pentanoic Acid Ethyl Ester

The product of Example 99 is prepared analogously to example 1 step 1,except 2-hydroxy-pentanoid acid ethyl ester is used instead of DL-leucicacid isopropyl ester as one of the starting materials and2-chloro-4-fluoro-benzonitrile is used instead of4-fluoro-2-trifluoromethyl-benzonitrile. The desired product is purifiedby column to yield an oily liquid as the pure product.

MS: 282.1M+1 for (C₁₄H₁₆ClNO₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.28 min. Purity 100%

Example 100 2-(2-Chloro-4-cyano-phenoxy)-pentanoic Acid Ethyl Ester

The product of Example 100 is prepared analogously to example 1 step 1,except 2-hydroxy-pentanoid acid ethyl ester is used instead of DL-leucicacid isopropyl ester as one of the starting materials and3-chloro-4-fluoro-benzonitrile is used instead of4-fluoro-2-trifluoromethyl-benzonitrile. The desired product is purifiedby column to yield a white solid as the pure product.

MS: 282.1M+1 for (C₁₄H₁₆ClNO₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.25 min. Purity 100%

Example 101 2-(3-Chloro-4-cyano-phenoxy)-pentanoic Acid[2-(1H-indol-3-yl)-ethyl]-amide

The product of Example 101 is prepared analogously to example 1,except: 1) in step 1, DL-2-hydroxy-pentanoic acid ethyl ester is usedinstead of DL-leucic acid isopropyl ester as one of the startingmaterials, 2) in step 1, 4-fluoro-2-chloro-benzonitrile is used in placeof 4-fluoro-2-trifluoromethyl-benzonitrile and 3) in step 3,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,1-hydroxy-benzotriazole, N-methylmorpholine and aminobenzylamine areused as the base/coupling agent. The desired product was purified bysilica gel column.

MS: 396.2 (M+1 for C₂₂H₂₂ClN₃O₂) LCMS: C-18 column (25% H₂O/75% CH₃CNRT=1.13 min. Purity 95.5%

Example 102 2-(3-Chloro-4-cyano-phenoxy)-pentanoic Acid Benzylamide

The product of Example 102 is prepared analogously to example 1,except: 1) in step 1, DL-2-hydroxy-pentanoic acid ethyl ester is usedinstead of DL-leucic acid isopropyl ester as one of the startingmaterials, 2) in step 1, 4-fluoro-2-chloro-benzonitrile is used in placeof 4-fluoro-2-trifluoromethyl-benzonitrile and 3) in step 3,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,1-hydroxy-benzotriazole, N-methylmorpholine and aminobenzylamine areused as the base/coupling agent. The desired product was purified bysilica gel column.

MS: 343.1 (M+1 for C₁₉H₁₉ClN₂O₂) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.20 min Purity 99.5%

Example 103 2-(3-Chloro-4-cyano-phenoxy)-pentanoic Acid[2-(4-hydroxy-phenyl)-ethyl]-amide

The product of Example 103 is prepared analogously to example 1,except: 1) in step 1, DL-2-hydroxy-pentanoic acid ethyl ester is usedinstead of DL-leucic acid isopropyl ester as one of the startingmaterials, 2) in step 1, 4-fluoro-2-chloro-benzonitrile is used in placeof 4-fluoro-2-trifluoromethyl-benzonitrile and 3) in step 3,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,1-hydroxy-benzotriazole, N-methylmorpholine and aminobenzylamine areused as the base/coupling agent. The desired product was purified bysilica gel column.

MS: 373.2 (M+1 for C₂₀H₂₁ClN₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=0.97 min. Purity 99.9%

Example 104 (S)-2-(3-Chloro-4-cyano-phenoxy)-pentanoic Acid Benzylamide

The product of Example 104 was prepared by chiral HPLC separation of theproduct of Example 102.

MS: 343.1 (M+1 for C₁₉H₁₉ClN₂O₂) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.23 min Purity 100%

Example 105 (S)-2-(3-Chloro-4-cyano-phenoxy)-pentanoic Acid[2-(4-hydroxy-phenyl)ethyl]amide

The product of Example 105 was prepared by chiral HPLC separation of theproduct of Example 103. MS: 373.1 (M+1 for C₂₀H₂₁ClN₂O₃) LCMS: C-18column (25% H₂O/75% CH₃CN. RT=0.91 min. Purity 99.9%

Example 106 (S)-2-(3-Chloro-4-cyano-phenoxy)-pentanoic Acid[2-(1H-indol-3-yl)-ethyl]-amide

The product of Example 106 was prepared by chiral HPLC separation of theproduct of Example 101.

MS: 396.1 (M+1 for C₂₂H₂₂ClN₃O₂) LCMS: C-18 column (25% H₂O/75% CH₃CNRT=1.11 min. Purity 100%

Example 107 (S)-2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoicacid-3-methyl-benzylamide

The product of Example 107 was prepared by chiral HPLC separation of theproduct of Example 43.

MS: 391.2 (M+1 for C₂₁H₂₁F₃N₂O₂) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.43 min. Purity 100%

Example 108 (S)-2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid{2-(1H-indol-3-yl)-ethyl]-amide

The product of Example 108 was prepared by chiral HPLC separation of theproduct of Example 65.

MS: 430.1 (M+1 for C₂₃H₂₂F₃N₃O₂) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.24 min. Purity 100%

Example 109 (S)-2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicacid-[2-(4-hydroxy-phenyl)-ethyl]-amide

The product of Example 109 was prepared by chiral HPLC separation of theproduct of Example 61.

MS: 407.2 (M+1 for C₂₁H₂₁F₃N₂O₃) LCMS: C-18 column (50% H₂O/50% CH₃CN.RT=0.94 min Purity 99.9%

Example 110 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid [1-(4-methoxy-phenyl)-ethyl]-amide

The product of Example 110 is prepared analogously to example 1,except: 1) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 2)1-4-methoxy-phenyl)-ethylamine is used instead of benzylamine. Thedesired product is purified by silica gel column.

MS: 435.1 (C₂₃H₂₅F₃N₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN. RT=1.48min. Purity 99.9%

Example 111 (R-)2(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid [2-4-hydroxy-phenyl)-ethyl]-amide

The product of Example 111 was prepared by chiral HPLC separation of theproduct of Example 61.

MS: 421.2 (M+1C₂₂H₂₃F₃N₂O₃) LCMS: C-18 column (50% H₂O/750 CH₃CN.RT=2.55 min. Purity 100%

Example 112 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid (1-phenyl-ethyl)-amide

The product of Example 112 is prepared analogously to example 1,except: 1) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 2)1-phenethylamine is used instead of benzylamine. The desired product ispurified by silica gel column.

MS: 405.1 (M+1 for C₂₂H₂₃F₃N₂O₂) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.51 min Purity 100%

Example 113 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid[1-(4-methoxy-phenyl)-ethyl]-amide

The product of Example 113 is prepared analogously to example 1,except: 1) in step 1, DL-2-hydroxy-pentanoic acid ethyl ester is usedinstead of DL-leucic acid isopropyl ester as one of the startingmaterials, 2) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 3)1-(4-methoxy-phenyl)-ethylamine is used instead of benzylamine. Thedesired product is purified by silica gel column:

MS: 421.1 (M+1 for C₂₂H₂₃F₃N₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.26 min. Purity 100%

Example 114 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid (2-ethyl sulfanyl-ethyl)-amide

The product of Example 114 is prepared analogously to example 1,except: 1) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 2)2-ethylsulfanyl-ethylamine is used instead of benzylamine. The desiredproduct is purified by silica gel column

MS: 389.1M+1 for (C₁₈H₂₃F₃N₂O₂S)

Example 115 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(3-propoxy-propyl)-amide

HPLC—Method C

LCMS—Method A

MS 387.24 (M+1 for C₁₉H₂₅F₃N₂O₃ Ret Time 3.9 min. Purity: 100%

Example 116 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid(3-hydroxy-4-methyl-phenyl)-amide

HPLC—Method C

LCMS—Method A

MS 393.21 (M+1) for C₂₀H₁₉F₃NO₃ Ret. Time 3.63 min. Purity 100%

Example 117 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid [1-(4-hydroxy-phenyl)-ethyl]-amide

The product of Example 117 is prepared analogously to example 1,except: 1) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 2)4-(1-amino-ethyl)phenol is used instead of benzylamine. The desiredproduct is purified by silica gel column.

MS: 421.1 (M+1 for C₂₂H₂₃F₃N₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.03 min. Purity 100%

Example 118 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid[1-(4-hydroxy-phenyl)-ethyl]-amide

The product of Example 118 is prepared analogously to example 1,except: 1) in step 1, DL-2-hydroxy-pentanoic acid ethyl ester is usedinstead of DL-leucic acid isopropyl ester as one of the startingmaterials, 2) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 3)4-(1-amino-ethyl)-phenol is used instead of benzylamine. The desiredproduct is purified by silica gel column:

MS: 407.1 (M+1 for C₂₁H₂₁F₃N₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=0.94 min. Purity 99.9%

Example 119 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid[1-(4-hydroxy-phenyl)-ethyl]-amide

The product of Example 119 is prepared analogously to example 1,except: 1) in step 1, DL-2-hydroxy-pentanoic acid ethyl ester is usedinstead of DL-leucic acid isopropyl ester as one of the startingmaterials, 2) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 3)4-(1-amino-ethyl)-phenol is used instead of benzylamine. The desiredproduct is purified by silica gel column:

MS: 407.1 (M+1 for C₂₁H₂₁F₃N₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=0.98 min. Purity 99.9%

Example 120 2-(4-cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid [1-(4-hydroxy-phenyl)-ethyl]-amide

The product of Example 117 is prepared analogously to example 1,except: 1) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 2)4-(1-amino-ethyl)phenol is used instead of benzylamine. The desiredproduct is purified by silica gel column.

MS: 421.1 (M+1 for C₂₂H₂₃F₃N₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN.RT=1.10 min. Purity 100%

Example 121 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid [1-(4-methoxy-phenyl)-ethyl]-amide

The product of Example 121 is prepared analogously to example 1,except: 1) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 2)1-(4-methoxy-phenyl)-ethylamine is used instead of benzylamine. Thedesired product is purified by silica gel column:

MS: 435.2 (M+1 for C₂₃H₂₅F₃N₂O₃ LCMS—C-18 column (25% H₂O/75% CH₃CN.RT=1.49 min. Purity 98.5%

Example 122 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoicAcid (1-phenyl-ethyl)-amide

The product of Example 122 is prepared analogously to example 1,except: 1) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 2) 1-phenylethylamine is used instead of benzylamine. The desired product ispurified by silica gel column.

MS: 405.1 (M+1 for C₂₃H₂₃F₃N₂O₂ LCMS—C-18 column (25% H₂O/75% CH₃CN.RT=1.60 min. Purity 99.5%

Example 123 2-(4-Cyano-3-trifluoromethyl-phenoxy)-pentanoic Acid[1-(4-methoxy-phenyl)-ethyl]-amide

The product of Example 123 is prepared analogously to example 1,except: 1) in step 1, DL-2-hydroxy-pentanoic acid ethyl ester is usedinstead of DL-leucic acid isopropyl ester as one of the startingmaterials, 2) in step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, 1-hydroxy-benzotriazole, N-methylmorpholine andaminobenzylamine are used as the base/coupling agent and 3)1-(4-methoxy-phenyl)-ethylamine is used instead of benzylamine. Thedesired product is purified by silica gel column.

MS: 421.1 (C₂₂H₂₃F₃N₂O₃) LCMS: C-18 column (25% H₂O/75% CH₃CN. RT=1.26min Purity 100%

Example 124

The compounds of Formula I have affinity for the androgen receptor. Thisaffinity has been demonstrated for selected compounds using the humanreceptor. The description below describes how the assay was carried out.

Competitive binding analysis was performed on baculovirus/Sf9 generatedhAR extracts in the presence or absence of different concentrations oftest agent and a fixed concentration of ³H-dihydrotestosterone (³H-DHT)as tracer. This binding assay method is a modification of a protocolpreviously described (Liao S., et. al. J. Steroid Biochem. 20:11-171984). Briefly, progressively decreasing concentrations of compounds areincubated in the presence of hAR extract (Chang et al. P.N.A.S. Vol. 89,pp. 5546-5950, 1992), hydroxylapatite, and 1 nM³H-DHT for one hour at 4°C. Subsequently, the binding reactions are washed three times tocompletely remove excess unbound 3H-DHT. hAR bound ³H-DHT levels aredetermined in the presence of compounds (=i.e competitive binding) andcompared to levels bound when no competitor is present (=i.e. maximumbinding). Compound binding affinity to the hAR is expressed as theconcentration of compound at which one half of the maximum binding isinhibited. Table II below provides the results that were obtained forselected compounds (reported data is the mean of multiple tests as shownbelow)

TABLE II Example AR Binding # Structure IC₅₀ (nM) 1

 95 (c) 2

 64 (a) 3

 247 (a) 4

 445 N = 8 5

 277 (a) 6

 455 (a) 7

 107 (a) 8

 58 (a) 9

 163 (a) 10

 91 (a) 11

 172 (a) 12

 86 (a) 13

 240 (a) 14

 197 (a) 15

 309 (a) 16

 368(c) 17

1002 (a) 18

 222 (a) 19

 131 (a) 20

 410 (a) 21

 362 (a) 22

 178 (a) 23

UA 24

 56 (a) 25

 67 (c) 26

 67 (a) 27

 214 (a) 29

 180 (a) 30

 134 (a) 31

 83 (a) 32

 407 (a) 33

 62 (a) 34

 68 (a) 35

 77 (a) 36

 42 (a) 37

 41 (a) 38

 15 (a) 39

 42 (a) 40

 241 (a) 41

 171 (a) 42

 139 (a) 43

 99 (N = 9) 44

 42 (a) 45

 58 (a) 46

 103 (a) 47

 144 (a) 48

 123 (a) 49

 75 (a) 50

 399 (a) 51

 381 (a) 52

UA 53

 59 (a) 54

 70 (a) 55

 182 (a) 56

 157 (a) 57

 146 (a) 58

 64 (a) 59

 48 (c) 60

 318 (a) 61

 86 (N = 8) 62

 192 (a) 63

 482 (a) 64

 220 (a) 65

 33 (b) 66

 151 (N = 6) 67

 440 (a) 68

 223 (a) 69

 341 (a) 70

 253 (a) 71

 288 (a) 72

 82 (a) 73

 92 (a) 74

 139 (a) 75

 417 (a) 76

 479 (a) 77

 292 (a) 78

 121 (c) 79

3135 (c) 81

 142 (a) 82

 218 (a) 83

 85 (a) 84

 112 (a) 85

 117 (a) 86

 25 (a) 87

 119 (a) 88

 296 (c) 89

 486 (a) 90

 736 (a) 91

 70 (c) 92

 348 (c) 93

 485 (c) 94

 66 (b) 95

 126 (b) 96

 95 (a) 97

 111 (a) 98

 279 (a) 99

 31 (a) 100

 347 (a) 101

 53 (a) 102

 125 (c) 103

 140 (b) 104

 241 (c) 105

 241 (c) 106

 47 (a) 107

 93 (a) 108

 21 (a) 109

 251 (a) 110

 340 (c) 111

 148 (b) 112

 329 (a) 113

 654 (c) 114

 102 (a) 115

 428 (a) 116

 296 (c) 117

 114 (a) 118

1005 (c) 119

 86 (c) 120

 98 (a) 121

 145 (a) 122

 329 (a) 123

 653 (c) a-mean of 2 tests b-mean of 3 tests c-mean of 4 tests UA-dataunavailable ND-not determined

Example 124

The compounds ability to antagonize the effects of androgen on theandrogen receptor were determined in a whole cell assay as describedimmediately below.

Experimental Procedure for AR Antagonist Cell Assay

Cell line: MDA-MB453-MMTV clone 54-19. This cell line is a stabletransfected cell line with MDA-MB453 cell background (a human breasttumor cell line expressing androgen receptor). A MMTV minimal promotercontaining ARE was first cloned in front of a firefly luciferasereporter gene. Then the cascade was cloned into transfection vectorpUV120puro. Electroporation method was used for transfecting MDA-MB-453cell. Puromycin resistant stable cell line was selected.

Cell Culture Media and Reagents:

Culture medium: DMEM (high glucose, Gibco cat #: 11960-044), 10% FBS,and 1% L-glutamine

Plating medium: DMEM (phenol red free), 10% charcoal treated HyCloneserum, 1% L-glutamine

Assay medium: DMEM (phenol red free), 1% charcoal treated HyClone serum,1% L-glutamine, and 1% penicillin/streptomycin

3× luciferase buffer: 2% beta-mercaptoethanol, 0.6% ATP, 0.0135%luciferine in cell lysis buffer

Assay Procedure:

-   -   1. Cells are maintained in culture medium, splitting cells when        they reach 80-90% confluence    -   2. To test compounds, 10,000 cells/well are plated to opaque 96        cell culture plate in 100 ul/well plating medium, culture for        overnight at 37° C. in cell culture incubator    -   3. Carefully remove plating medium, then add 80 ul/well of        pre-warmed assay medium, add 10 ul/well testing compound (final        concentration at) 1000 nM, 200 nM, 40 nM, 8 nM, 1.6 nM, and 0.32        nM), incubate at 37° C. for 30 minutes    -   4. Add 10 ul/well freshly prepared DHT (final concentration at        100 pM) to each well, incubate at 37° C. for 17 hr (overnight)    -   5. Add 50 ul/well 3× luciferase buffer, incubate at room        temperature for 5 minutes, then count on Luminometer        The fold induction over background by 100 pM DHT in the absence        of testing compounds is standardized as 100% and experimental        result is expressed as percentage of inhibition by testing        compounds.

The results are described below in Table III. The results are reportedas the mean of multiple tests as described below (the numbers of testsare indicated in the footnote). N.D. denotes that the compound was nottested.

TABLE III Example AR Cell # Structure IC₅₀ (nM) 1

201 (c) 2

142 (c) 3

ND 4

57 (N = 6) 5

>1000 (a) 6

ND 7

661 (c) 8

534 (a) 9

>1000 (a) 10

>1000 (a) 11

>1000 (a) 12

>1000 (a) 13

398 (a) 14

>1000 (a) 15

>1000 (a) 16

ND 17

ND 18

815 (a) 19

>1000 (a) 20

ND 21

ND 22

>1000 (a) 23

UA 24

779 (a) 25

(798) (c) 26

>1000 (a) 27

ND 29

>1000 (a) 30

355 c) 31

>1000 (a) 32

ND 33

864 (a) 34

>1000 (a) 35

768 (a) 36

>1000 (a) 37

>1000 (a) 38

>1000 (a) 39

>1000 (a) 40

ND 41

130 (N = 6) 42

>1000 (a) 43

105 (c) 44

37 (c) 45

>1000 (a) 46

638 (a) 47

>1000 (a) 48

>1000 (a) 49

>1000 (a) 50

ND 51

ND 52

UA 53

299 (a) 54

836 (a) 55

393 (a) 56

790 (a) 57

561 (a) 58

>1000 (a) 59

101 (a) 60

ND 61

341 (N = 10) 62

>1000 (a) 63

ND 64

>1000 (a) 65

64 (N = 6) 66

77 (N = 10) 67

ND 68

>1000 (a) 69

ND 70

ND 71

ND 72

251 (c) 73

428 (a) 74

976 (c) 75

ND 76

ND 77

ND 78

948 (a) 79

>1000 (a) 81

>1000 (a) 82

>1000 (a) 83

>1000 (a) 84

>1000 (a) 85

>1000 (a) 86

>1000 (a) 87

>1000 (a) 88

ND 89

ND 90

ND 91

535 (c) 92

562 (a) 93

563 (a) 94

140 (c) 95

32 (c) 96

138 (a) 97

26 (a) 98

N.D. 99

749 (a) 100

ND 101

38 (a) 102

27 (c) 103

87 (c) 104

7 (c) 105

88 (c) 106

3 (a) 107

<0.32 (a) 108

<0.32 (a) 109

58 (a) 110

ND 111

164 (c) 112

ND 113

681 (a) 114

727 (a) 115

ND 116

ND 116

ND 117

19 (a) 118

589 (a) 119

117 (a) 120

44 (c) 121

157 (c) 122

ND 123

681 (a) a—mean of two tests b—mean of three tests c—mean of four testsUA—unavailable ND—not determined

Example 126 Animal Model for Androgenetic Alopecia

As described above, alopecia is a problem that medical science hasdevoted considerable resources to. As with any disease process, animalmodels have been developed to allow scientists to screen compounds fortheir potential relative efficacy. Those compounds showing the greatestefficacy in these animal models are considered for further study inhumans. Two different animal models have been developed to date foralopecia. The first is the telogen conversion assay, which uses femaleC3H/HeN mice. The second model uses stump-tailed macaques, which aremonkeys that suffer from androgenetic alopecia.

The telogen conversion assay measures the potential of a compound toconvert the resting stage of the hair growth cycle (“telogen”) to theactive stage of the hair growth cycle (“anagen”) in mice. This assaytakes advantage of the fact that the fur (i.e. hair) of 7-week-oldC3H/HeN mice is in the telogen phase. This phase continues until about75 days of age. In this assay, selected areas of the mice are shaved,contacted with a test agent, or a control, and the difference in therate of hair growth is measured (i.e. induction of the anagen phase).The first sign of anagen is the darkening of skin color as melanocytesin the follicles start to synthesize melanin, in preparation for theproduction of pigmented hairs. This model has a number of advantages.This includes the ready availability of female CH3HeN mice, the abilityto screen large numbers of compounds quickly, and the ease of housingand handling such animals.

The primary disadvantage of this model is its lack of androgeneticdependency. While the exact cause of human baldness is not known, it iswell documented that androgens induce a regression of hair follicles inthe scalp. This post adolescent regressive change is a fundamental causeof male pattern baldness, (i.e. “androgenetic alopecia). This phenomenonoccurs in both men and women who have inherited the genetic trait foralopecia, as mentioned previously. For a more detail discussion of theeffects of androgens on human scalps, the readers attention is directedto Trueb, R M, Molecular Mechanisms of Androgenic Alopecia, Exp.Gerontology, 2002, 27:981-990.

Researchers looked for other animals whose hair growth was similar tothat of humans. These lead researchers to stump-tailed macaques. Theseprimates also suffer from androgenetic alopecia. Essentially all postadolescent macaques, in both sexes, exhibit the development of baldness.Like the development of male pattern baldness in humans, androgens arean indispensable triggering factor in macaque baldness. Thinning of thefrontal scalp hairs begins to appear around the same age (4 years) whenserum levels of testosterone become drastically elevated in maleanimals. Although the elevation of testosterone in females isapproximately one tenth that of the male level, there is no differencein the incidence and the age of onset of baldness between male andfemale stump-tailed macaques. Topical application of anti-androgens havereversed this baldness in animals of both sexes (Pan, H J et al,Evaluation of RU58841 as an anti-androgen in prostate PC3 cells and atopical anti-alopecia agent in the bald scalp of stump tailed macaques.Endocrine 1998; 9:39-43).

While this model is a significant improvement over the telogenconversion assay as a model for human baldness, it suffers from a numberof practical disadvantages. The macaques are expensive, relatively rare,labor intensive to maintain, and require long wash out periods betweentesting. Thus, the macaque is not a practical model for screening largenumbers of compounds

It has been discovered that male C3H/HeN mice may be used in the telogenconversion assay, when evaluating anti-androgen test compounds. Thus,the model relates to a modification of the existing telogen conversionassay. Male C3H/HeN mice approximately 7 weeks old are utilized. Theseanimals are also uniformly in telogen, like their female counterparts.However, once shaven, the androgens inherently present in these malemice inhibit the conversion of the hair follicles to the anagen phase.An anti-androgen will block this androgenic effect and the follicleswill convert to anagen, like their female counterparts.

Example 126A

The compound described in Example 1 was submitted for further testingutilizing the modified telogen conversion assay, described above. Thetesting was carried out in the following manner.

Male C3H/HeN mice, 6 to 7 weeks old (Charles River Laboratories,Raleigh, N.C.) were used for the study. Fur was clipped from the dorsalregion of the mice prior to initiation of the study. Only mice with pinkskin, a visual indication of the telogen phase, were selected forinclusion in the study.

The test compound was dissolved in a vehicle consisting of propyleneglycol (30%) and ethanol (70%) to achieve concentrations of 1% and 4%w/v. The relevant dose was applied topically to the clipped dorsalregion of the mice in one test group (7-10 mice) in a volume of 20μl/cm². A third group of animals received only the vehicle to serve as acontrol. Treatments were applied twice daily for 4 weeks.

The treatment area was observed and graded every other day for signs ofhair growth. The hair growth response was quantified by recording, foreach animal, the day on which signs of hair growth first appeared overthe treated area. The first sign of anagen was the darkening of skincolor as melanocytes in the follicles started to synthesize melanin inpreparation for the production of pigmented hairs. The mice wereobserved for 35 days or longer.

As shown in FIG. 1, the product of Example 1 was active atconcentrations of both 1% and 4%. Anagen was initiated in each of thetest groups prior to its occurrence in the control group.

Example 126B

The protocol described above in Example 98A was repeated for the productof Example 4 at a concentration of 3 w/v %. Anagen did not occur in thetest group prior to its initiation in the vehicle control group.

Example 127 Animal Model for Inhibition of Sebum Production

Luderschmidt et al describes an animal model for testing whethercompounds are capable of modulating sebum secretion. Arch. Derm. Res.258, 185-191 (1977). This model uses male Syrian hamsters, whose earscontain sebaceous glands. The products of Example 1 and 4 were screenedin this model.

Testing for sebum inhibition was carried out in the following manner.Male Syrian hamsters aged 9 to 10 weeks were introduced into thelaboratory environment and acclimated for 2 weeks prior to use in thestudy. Each group consisted of 5 animals and run in parallel withvehicle and positive controls. Prior to administration, 30 mg of eachcompound was dissolved in 1 mL of a solvent consisting of transcutanol,ethanol, and propylene glycol (20/60/20% v/v) to achieve a finalconcentration of 3-w/v %.

Animals were dosed topically twice daily, five days a week, for 4 weeks.Each dose consisted of 25 micro liters of vehicle control or drug. Thedose was applied to the ventral surfaces of both the right and leftears. All animals were sacrificed approximately 18-24 hours after thefinal dose. The right ears were collected from each animal and used forsebum analysis.

The ears were prepped for HPLC analysis in the following manner. One 8mm distal biopsy punch was taken, just above the anatomical “V” mark inthe ear to normalize the sample area. The punch was pulled apart. Theventral biopsy surface (the area where the topical dose was directlyapplied to the sebaceous glands) was retained for testing and the dorsalsurface of the biopsy punch was discarded.

Tissue samples were blown with N₂ gas and stored at −80° C. undernitrogen until HPLC analysis. In addition to ear samples, an aliquot ofeach drug and vehicle (at least 250 ul) was also stored at −80° C. forinclusion in the HPLC analysis.

HPLC analysis was carried out on an extract of the tissue sample. Tissuesamples were contacted with 3 ml of solvent (a 4:1 admixture of2,2,4-trimethylpentane and isopropyl alcohol). The mixture was shakenfor 15 minutes and stored overnight at room temperature, protected fromlight. The next morning 1 milliliter of water was added to the sampleand shaken for 15 minutes. The sample was then centrifuged atapproximately 1500 rpm for 15 minutes. Two ml of the organic phase (toplayer) was transferred to a glass vial, dried at 37° C., under nitrogen,for approximately 1 hour, and then lyophilized for approximately 48hours. The samples were then removed from the lyophilizer and each vialwas reconstituted with 600 μl of solvent A(trimethylpentane/tetrahydrofuran (99:1). The samples were then recappedand vortexed for 5 minutes.

200 μl of each sample was then transferred to a pre-labeled 200 μl HPLCvial with 200 μL glass inserts. The HPLC vials were placed in theautosampler tray for the Agilent 1100 series HPLC unit. The Agilent 1100HPLC system consisted of a thermostated autosampler, a quarternary pump,a column heater, and an A/D interface module. All components werecontrolled by Agilent ChemStation software. A Waters Spherisorb S3W4.6×100 mm analytical column was maintained at 30° C. by the Agilentcolumn heater unit. The HPLC autosampler was programmed to maintain thesample temperature at 20 C throughout the run.

10 uL of each sample was injected in triplicate into the column. Twosolvents were used for the solvent gradient. Solvent A was an admixtureof trimethylpentane and tetrahydrofuran (99:1). Solvent B wasethylacetate. The gradient utilized is described in the table below:

Time (min) Solv A (%) Solv B (%) Flow (mL/min) 0 99 1 2 2 96 4 2 6 60 402 7 5 95 2 10 5 95 2 10.1 99 1 2

The Sedex 75 Evaporative Light Scattering Detector (ELSD) was operatedat 45° C. with a gain of 5, and N₂ pressure maintained at 3.1 bar.Analog signal obtained by the instrument was sent to the Agilent A/Dinterface module where it was converted to a digital output. Theconversion was based on a 10000-mAU/volt set point and the data rate wasset at 10 Hz (0.03 min). The resulting digital output was then feed intothe Agilent ChemStation software for integration of the peak area.

The results of the HPLC analysis are reported below in Table IV. Theresults are reported as the reduction in cholesterol ester (CE) and waxester (WE) production, when compared to the vehicle control.

% % Reduction Reduction Sum Compound Structure in CE in WE CE + WEExample 1

32% 52% 84% Example 4

15% 31% 46%

Columns 1 and 2 identify the compound by structure and Example number.Columns 3 through 5 show the effect the compounds had on the reductionof sebum components (CE and WE). The results are expressed as thedifference from the vehicle control. A positive number reflects adecrease in the production of the sebum component being measured, i.e.cholesterol esters (CE) or wax esters (WE).

Column 3 shows the compounds ability to reduce the amount of cholesterolester in the sebum sample. Column 4 shows the effect the compound had onthe generation of wax ester. Wax esters are specific markers of thesebaceous glands and are not appreciably detected in any other layer ofthe skin. Wax ester is the largest component of sebum (approximately25%). Thus reducing wax ester typically leads to significant reductionsin sebum secretion. Column 5 is a summation of the results expressed incolumns 3 and 4 (and is included to further elucidate relativedifferences in activity). As shown in Table IV, the androgen modulatorsof Formula I significantly decreased the production of cholesterolesters and wax esters.

1. A compound of the formula:

in which; a) X¹ is represented by cyano, halogen or haloalkyl, b) R¹ andR² are each independently represented by hydrogen or (C₁-C₆) alkyl,optionally substituted, c) Alk¹ is represented by a C₁-C₂ linearalkylene group, in which up to two hydrogen atoms are optionallyreplaced by a substituent selected from the group consisting of C₁-C₆alkyl optionally substituted, halogen, hydroxy, thiol, and cyano, d) nis represented by the integer 0 or 1, e) Y is represented by NX²X³ orO—X³, f) X² is represented by hydrogen or (C₁-C₆) alkyl optionallysubstituted, g) X³ is represented by i. hydrogen, ii. (C₁-C₁₂)alkyl,optionally substituted, iii. (C₂-C₁₂)alkenyl, optionally substituted,iv. (C₂-C₁₂)alkynyl, optionally substituted, v. (C₃-C₁₀)cycloalkyl,optionally substituted, vi. (C₃-C₁₀) cycloalkyl(C₁-C₆)alkyl, in whichthe alkyl and cycloalkyl moieties may each be optionally substituted,vii. (C₆-C₁₀)aryl, optionally substituted, viii.(C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and aryl moieties may eachbe optionally substituted, ix. —(CH₂)-(Alk²)_(q)-C(O)R³, in which Alk²is represented by a (C₁-C₈) linear alkylene group, in which up to eighthydrogen atoms may optionally be replaced by a substituent, selectedfrom the group consisting of (C₁-C₆) alkyl optionally substituted,(C₁-C₆) alkoxy, halogen, hydroxy, thiol, cyano, and NR⁸R⁹ in which R⁸and R⁹ are each independently represented by hydrogen or (C₁-C₆) alkyl,q is the integer 0 or 1, R³ is represented by hydrogen, (C₁-C₁₂)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and arylmoieties may each be optionally substituted, x.—(CH₂)-(Alk²)_(q)-C(O)—O—R⁴, in which Alk² and q, are as defined above,and R⁴ is represented by hydrogen, (C₁-C₁₂)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and aryl moieties may beoptionally substituted, xi. —(CH₂)-(Alk²)_(q)-C(O)—NR⁵R⁶ in which Alk²and q are as described above, and R⁵ and R⁶ are each independentlyrepresented by hydrogen, (C₁-C₁₂)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and aryl moieties may beoptionally substituted, xii. —(CH₂)-(Alk²)_(q)-Y—R⁷, in which Alk² and qare as defined above, Y is O or S, and R⁷ is selected from the groupconsisting of hydrogen, (C₁-C₁₂)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl, in which the alkyl and aryl moieties may beoptionally substituted, xiii. heteroaryl, optionally substituted, xiv.heteroaryl(C₁-C₆)alkyl, in which the heteroaryl and alkyl moieties mayeach be optionally substituted, xv. heterocyclic, optionallysubstituted, xvi. heterocyclic(C₁-C₆)alkyl, in which the alkyl andheterocyclic moieties may each be substituted, or, h) for thosecompounds in which Y is N, X² and X³, along with the adjacent nitrogenatom, may form a heterocyclic ring, which may optionally be substituted,or a salt, solvate, or prodrug thereof.
 2. A compound according to claim1 in which one of R¹ or R² is hydrogen and the other of R¹ or R² isselected from the group consisting of isobutyl, propyl, n-butyl,isopropyl, and ethyl.
 3. A compound according to claim 1 or 2 in which nis
 0. 4. A compound according to claim 1, 2, or 3 in which X¹ istrifluoromethyl and is located at the 3-position of the phenyl ring. 5.A compound according to claim 1, 2, 3, or 4 in which Y is NX²X³.
 6. Acompound according to claim 5 in which X² is hydrogen.
 7. A compoundaccording to claim 6 in which X³ is represented by a substituentselected from the group consisting of (C₁-C₁₂)alkyl,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆alkyl,heteroaryl(C₁-C₆)alkyl, and heterocyclic(C₁-C₆)alkyl.
 8. A compoundaccording to claim 1, 2, 3, or 4 in which Y is OX³.
 9. A compoundaccording to anyone of claims 1-8 in which X¹ is represented by halogenor haloalkyl.
 10. Use of a compound according to anyone of claims 1-9 asa medicine.
 11. Use of a compound according to anyone of claims 1-9 inthe manufacture of a medicament for inhibiting activation of theandrogen receptor
 12. Use of a compound according to anyone of claims1-9 in the manufacture of a medicament for the alleviating a conditionselected from the group consisting of hormone dependent cancers, benignhyperplasia of the prostate, acne, hirsutism, excess sebum, alopecia,premenstrual syndrome, lung cancer, precocious puberty, osteoporosis,hypogonadism, age-related decrease in muscle mass, and anemia.
 13. Apharmaceutical composition comprising a compound according to anyone ofclaims 1-9 in admixture with 1, or more, pharmaceutically acceptableexcipients.
 14. A topical pharmaceutical formulation comprising acompound according to anyone of claims 1-9 in admixture with 1, or more,pharmaceutically acceptable excipients suitable for dermal application.15. An article of manufacture comprising a compound according to anyoneof claims 1-9 packaged for retail distribution, which advises a consumerhow to utilize the compound to alleviate a condition selected from thegroup consisting of acne, alopecia, and oily skin.